Naphthyridine derivatives having inhibitory activity against HIV integrase

ABSTRACT

A compound having HIV Integrase Inhibitory activity of the formula: 
                         
(wherein:
     R 1  is optionally substituted aralkyl;   R 2  and R 3  are each independently hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkenyl or optionally substituted alkoxy (provided that each substituent for “optionally substituted” is a noncyclic group);   R 4  is hydrogen, optionally substituted carboxy, optionally substituted formylamino, optionally substituted carbamoyl, optionally substituted amino (provided that a substituent on amino in “optionally substituted formylamino”, “optionally substituted carbamoyl” and “optionally substituted amino” may form an optionally-substituted N-atom containing heterocyclic ring together with an adjacent N atom), optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted heteroaryl) or a salt thereof.

TECHNICAL FIELD

The present invention relates to novel compounds having antiviralactivities, in detail naphthyridine derivatives having inhibitoryactivity against HIV integrase and a pharmaceutical composition,especially an anti-HIV agent, containing the same.

BACKGROUND ART

Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus,is known to cause acquired immunodeficiency syndrome (AIDS). Thetherapeutic agent for AIDS is mainly selected from a group of reversetranscriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g.,Indinavir), but they are proved to be accompanied by side effects suchas nephropathy and the emergence of resistant viruses. Thus, thedevelopment of anti-HIV agents having the other mechanism of action hasbeen desired.

On the other hand, a multidrug combination therapy is reported to beefficient in treatment for acquired immunodeficiency syndrome (AIDS)because of the frequent emergence of the resistant mutant. Reversetranscriptase inhibitors and protease inhibitors are clinically used asan anti-HIV agent, however agents having the same mechanism of actionoften exhibit cross-resistance or only an additional activity.Therefore, anti-HIV agents having the other mechanism of action aredesired.

As a compound having inhibitory activity against HIV integrase,1,6-naphthyridine derivative is known (see Patent documents 1 to 7). Thederivative has a cyclic group such as aryl or heteroaryl at 7-positionof side chain end.

Also a 1,6-naphthyridine derivative having a similar structure to thecompound of the present invention was internationally filed by thepresent applicant (see Patent document 8).

-   [Patent document 1]-   WO 2002/30426-   [Patent document 2]-   WO 2002/30930-   [Patent document 3]-   WO 2002/30931-   [Patent document 4]-   WO 2002/36734-   [Patent document 5]-   WO 2002/44079-   [Patent document 6]-   WO2003/77850-   [Patent document 7]-   WO2003/77857-   [Patent document 8]-   PCT/JP 03/10212

Under the above circumstance, the development of a novel integraseinhibitor has been desired.

DISCLOSURE OF INVENTION

The present inventors have intensively studied to find that a novelnaphthyridine derivative has a strong inhibitory activity against HIVintegrase. Moreover, the present inventors have discovered that acompound of the present invention and a pharmaceutical compositioncontaining the same are useful as an antiviral agent (e.g., anantiretroviral agent, an anti-HIV agent, an anti-HTLV-1 (Human T cellleukemia virus type 1) agent, an anti-FIV (Feline immunodeficiencyvirus) agent or an anti-SIV (Simian immunodeficiency virus) agent),especially an anti-HIV agent or, an anti-AIDS agent, pharmaceuticalagents for related diseases and the like, to accomplish the presentinvention.

Specifically, the present invention relates to the following inventivefeatures:

-   (1) A compound of the formula:

(wherein:

-   R¹ is optionally substituted aralkyl;-   R² and R³ are each independently hydrogen, optionally substituted    alkyl, optionally substituted amino, optionally substituted alkenyl    or optionally substituted alkoxy (provided that each substituent for    “optionally substituted” is a noncyclic group);-   R⁴ is hydrogen, optionally substituted carboxy, optionally    substituted formylamino, optionally substituted carbamoyl,    optionally substituted amino (provided that a substituent on amino    in “optionally substituted formylamino”, “optionally substituted    carbamoyl” and “optionally substituted amino” may form an    optionally-substituted N-atom containing heterocyclic ring together    with an adjacent N atom), optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted aryl, or optionally    substituted heteroaryl), a pharmaceutically acceptable salt or a    solvate thereof (except for Compound (I-A) shown in Table 1 below).

TABLE 1 (I-A)

Compound No. R² R³ R⁴ 20 H CH2CH2OMe H 27 H Me NHMs 28 H CH2CH2OMe NHMs29 H i-Pr NHMs 85 Me Me H 86 H NHMe H 87 H NMe2 H 88 H OMe H 89 H H H 90H Me H 91 H Et H 92 H i-Pr H 126 H CH2CH2NMe2 H 160 H CH2CH2OMeNHCOCH2OMe 161 H CH2CH2OMe NHCOCH2CH2CO2Et 162 H CH2CH2OMe NHCOCH2CO2Et163 H CH2CH2OMe NHCOOEt 164 H CH2CH2OMe NHCOCH2CH2OMe 165 H CH2CH2OMeNHCO-thiophene 180 H CH2CH2OMe Ph-CH2OH 181 H NMe2 Ph-CH2OH (Me =methyl; i-Pr = isopropyl; Et = ethyl; Ms = methanesulfonyl; thiophene =thiophene; Ph = phenyl)

The above Compound (I-A) is an exemplary amide-type compound having a1,6-naphthyridine scaffold disclosed in PCT/JP03/10212.

-   (2) The compound according to the above (1), wherein R¹ is    p-fluorobenzyl, a pharmaceutically acceptable salt or a solvate    thereof.-   (3) The compound according to the above (1), wherein R² is hydrogen;    R³ is optionally substituted alkyl (substituent: lower alkoxy, amino    optionally substituted with lower alkyl, cyano, hydroxy, carboxy, or    lower alkoxycarbonyl), or optionally substituted amino (substituent:    lower alkyl), a pharmaceutically acceptable salt or a solvate    thereof.-   (4) The compound according to the above (1), wherein R² is hydrogen;    R³ is CH₂CH₂OCH₃, CH₂CH₂OEt, CH₂CH₂COOCH₃, CH₂CH₂CH₂OCH₃,    CH₂CH₂CH₂O(i-Pr), N(CH₃)₂, CH₂CH₂CN, CH₂CH₂N(CH₃)₂, CH₂CH₂N(i-Pr)₂,    CH₂CH₂CH₂N(CH₃)₂, CH₂CH₂CH₂N(Et)₂, CH(CH₃)CH₂OH, CH(CH₃)COOCH₃ or    CH₂CH(OH)CH₂CH₃, a pharmaceutically acceptable salt or a solvate    thereof.-   (5) The compound according to the above (1), wherein R⁴ is    optionally substituted carboxy, optionally substituted carbamoyl    (provided that the substituent on amino may form an    optionally-substituted N-atom containing heterocyclic ring together    with an adjacent N atom), optionally substituted formylamino,    optionally substituted alkyl, optionally substituted alkenyl or    optionally substituted heteroaryl, a pharmaceutically acceptable    salt or a solvate thereof.-   (6) The compound according to the above (1), wherein in R⁴,

a substituent for “optionally substituted carboxy” is lower alkyl,hydroxy lower alkyl, lower alkoxy lower alkyl, optionally substitutedamino lower alkyl, or optionally substituted heterocyclic group;

a substituent for “optionally substituted formylamino” is lower alkyl,hydroxy lower alkyl, lower alkoxy lower alkyl, optionally substitutedcarbamoyl lower alkyl, optionally substituted lower alkoxy, optionallysubstituted amino, or optionally substituted carbamoyl;

a substituent for “optionally substituted carbamoyl” is lower alkyl,optionally substituted lower alkyl (substituent: hydroxy, lower alkoxy,optionally substituted amino, optionally substituted lower alkoxy,carbamoyl), optionally substituted heterocyclic group, optionallysubstituted heterocyclic group lower alkyl, optionally substituted aryl,optionally substituted aryloxy lower alkyl, optionally substitutedaralkyl, optionally substituted carbamoyl lower alkyl, optionallysubstituted lower alkoxy, optionally substituted amino, optionallysubstituted alkenyl, or optionally substituted alkynyl;

a substituent for “optionally substituted amino” is lower alkyl, hydroxylower alkyl, lower alkoxy lower alkyl, optionally substitutedheterocyclic group, or optionally substituted carbamoyl lower alkyl;

a substituent for “optionally substituted alkyl” or “optionallysubstituted alkenyl” is hydroxy, halogen, optionally substitutedheterocyclic group, optionally substituted lower alkoxy, optionallysubstituted amino, optionally substituted carbamoyl, or optionallysubstituted carboxy;

a substituent for “optionally substituted aryl” or “optionallysubstituted heteroaryl” is hydroxy, lower alkyl, hydroxy lower alkyl,lower alkoxy lower alkyl, optionally substituted aminoalkyl, optionallysubstituted carbamoyl lower alkyl, optionally substituted lower alkoxy,optionally substituted amino, optionally substituted carbamoyl,optionally substituted alkenyl, optionally substituted carboxy,optionally substituted carboxyalkyl, optionally substituted salfamoyl,or optionally substituted salfamoylalkyl (provided that a substituent onamino in “optionally substituted formylamino”, “optionally substitutedamino” or “optionally substituted carbamoyl” may form anoptionally-substituted N-atom containing heterocyclic ring together withan adjacent N atom), a pharmaceutically acceptable salt or a solvatethereof.

-   (7) The compound according to the above (1), wherein R⁴ is a group    shown below, a pharmaceutically acceptable salt or a solvate    thereof.

(wherein, Me is methyl; Ac is acetyl; Ms is methanesulfonyl)

-   (8) The compound according to the above (1), wherein R¹ is    p-fluorobenzyl and R⁴ is a group described in the above (5), a    pharmaceutically acceptable salt or a solvate thereof.-   (9) The compound according to the above (1), wherein R¹ is    p-fluorobenzyl and R⁴ is a group described in the above (7), a    pharmaceutically acceptable salt or a solvate thereof.-   (10) The compound according to the above (1), wherein R¹ is    p-fluorobenzyl; R² is hydrogen; R³ is CH₂CH₂OCH₃, N(CH₃)₂, CH₂CH₂CN,    CH₂CH₂N(CH₃)₂, CH₂CH₂CH₂N(CH₃)₂, or CH₂CH(OH)CH₂CH₃; R⁴ is a group    described in the above (7), a pharmaceutically acceptable salt or a    solvate thereof.-   (11) A pharmaceutical composition comprising the compound according    to any of the above (1) to (10), a pharmaceutically acceptable salt    or a solvate thereof.-   (12) A pharmaceutical composition according to the above (11),    wherein it is a HIV integrase inhibitor.

EFFECT OF THE INVENTION

Compounds of the present invention have inhibitory activity againstintegrase, and/or have activity of inhibiting proliferation of viruses,especially HIV.

Therefore, they are useful for prophylaxis and therapy of a variety ofintegrase-related diseases, and viral infectious diseases (e.g., AIDS).

BEST MODE FOR CARRYING OUT THE INVENTION

The terms used in the present specification are explained as follows.Each term by itself or as part of another has the following meaning.

The term “alkyl” means preferably a C1-C10 straight or branched alkylgroup, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.More preferred is a lower (C1-C6) alkyl group, and more preferred is aC1-C4 lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl n-pentyl, isopentyl, neopentyl,tert-pentyl, n-hexyl or isohexyl.

The term “alkenyl” means a C2-C10 straight or branched alkenyl groupwhich is the above “alkyl” having one or more double bonds, for example,vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1,3-butadienyl or 3-methyl-2-butenyl.

The term “cycloalkyl” means a C3-C10 cyclic saturated hydrocarbon group,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl. Preferred is a C3-C6 cycloalkyl group.

An alkyl moiety of “alkoxy” has the same meanings as the above “alkyl”,and includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy and the like.

The term “aryl” means a monocyclic aromatic hydrocarbon group (e.g.,phenyl) or a polycyclic aromatic hydrocarbon group (e.g., 1-naphthyl,2-naphthyl, 1-antolyl, 2-antolyl, 9-antolyl, 1-phenantolyl,2-phenantolyl, 3-phenantolyl, 4-phenantolyl or 9-phenantolyl). Preferredis phenyl or naphthyl (e.g., 1-naphthyl or 2-naphthyl).

The term “aralkyl” means the above “alkyl” to which “aryl” is bound, forexample, benzyl, phenylthyl, phenylpropyl, α-naphthylmethyl orβ-naphthylmethyl. Preferred is benzyl.

The term “heterocyclic group” means “heterocycle” or “heteroaryl”.

The term “heterocycle” means a non-aromatic heterocyclic group(preferably 5 to 7-membered) which contains at least one of nitrogenatom, oxygen atom and sulfur atom, and which has a bonding position atany substitutable position, for example, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl,2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino ortetrahydropyranyl. Then, “a non-aromatic heterocyclic group” can besaturated or unsaturated insofar as it is non-aromatic.

The term “heteroaryl” means a monocyclic aromatic heterocyclic group anda condensed aromatic heterocyclic group.

A monocycle aromatic heterocyclic group means a group, which is derivedfrom a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygenatom, sulfur atom, and/or nitrogen atom and which may have a bondingposition at any substitutable position.

A condensed aromatic heterocyclic group means a group, wherein a 5- to8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfuratom, and/or nitrogen atom is condensed with 1 to 4 of 5- to 8-memberedaromatic carbon ring or the other 5- to 8-membered aromatic hetero ringand which may have a bonding position at the any substitutable position.

The term “heteroaryl” means the following groups, for example, furyl(e.g., 2-furyl or 3-furyl), thienyl (e.g., 2-thienyl or 3-thienyl),pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl or 4-imidazolyl), pyrazolyl (e.g.,1-pyrazolyl, 3-pyrazolyl or 4-pyrazolyl), triazolyl (e.g.,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-4-yl),tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl or 5-tetrazolyl), oxazolyl(e.g., 2-oxazolyl, 4-oxazolyl or 5-oxazolyl), isoxazolyl (e.g.,3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl or 5-thiazolyl), thiadiazolyl, isothiazolyl(e.g., 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl), pyridyl (e.g.,2-pyridyl, 3-pyridyl or 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl or4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl or5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g.,2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), benzofuryl(e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl,5-benzo[b]furyl, 6-benzo[b]furyl or 7-benzo[b]furyl), benzothienyl(e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl,5-benzo[b]thienyl, 6-benzo[b]thienyl or 7-benzo[b]thienyl),benzimidazolyl (e.g., 1-benzoimidazolyl, 2-benzoimidazolyl,4-benzoimidazolyl or 5-benzoimidazolyl), dibenzofuryl, benzooxazolyl,quinoxalyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl or 6-quinoxalinyl),cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl,6-cinnolinyl, 7-cinnolinyl or 8-cinnolinyl), quinazolyl (e.g.,2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl,7-quinazolinyl or 8-quinazolinyl), quinolyl (e.g., 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl or6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or8-isoquinolyl), puryl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl,6-pteridinyl or 7-pteridinyl), carbazolyl, phenantridinyl, acridinyl(e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl or9-acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl or 7-indolyl), isoindolyl, phanazinyl (e.g.,1-phenazinyl or 2-phenazinyl) or phenothiazinyl (e.g., 1-phenothiazinyl,2-phenothiazinyl, 3-phenothiazinyl or 4-phenothiazinyl).

As the “heterocyclic ring”, rings similar to those described above areexemplified.

When a specific group has a substituent, the substituent may beidentical or different 1 to 4 substituents selected from the substituentgroup B listed below.

Substituent group B: hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyl(e.g., CF₃, CH₂CF₃, CH₂CCl₃), alkyl (e.g., methyl, ethyl, isoproopyl,tert-butyl), optionally substituted alkenyl (e.g., vinyl), optionallysubstituted alkynyl (e.g., ethynyl), hydroxy lower alkyl, alkoxyalkyl,optionally substituted amino lower alkyl, optionally substitutedcarbamoyl lower alkyl, cycloalkyl (e.g., cyclopropyl), cycloalkenyl(e.g., cyclopropenyl), optionally substituted alkoxyl (e.g., methoxy,ethoxy, propoxy, butoxy), alkenyloxy (e.g., vinyloxy, allyloxy),alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl), hydroxy lower alkoxy, lower alkoxy lower alkoxy,nitro, nitroso, optionally substituted amino (e.g., amino, alkylamino(e.g., methylamino, ethylamino, dimethylamino), acylamino (e.g.,acetylamino, benzoylamino), aralkylamino (e.g., benzylamino,tritylamino), hydroxyamino, lower alkyl carbonyl amino, loweralkenylamino), azide, aryl (e.g., phenyl), aralkyl (e.g., benzyl),cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto,alkylthio (e.g., methylthio), hydroxy alkylthio, alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl), optionally substituted carbamoyl(e.g., alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl)), sulfamoyl, acyl (e.g., formyl, lower alkylcarbonyl(e.g., acetyl)), formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy,dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino,azide, ureido, amidino, guanidino, phthalimide, oxo, imino, —SO₂OH,COCONH₂, CSNH₂, thiocarbonyl optionally substituted with lower alkyl,cyano lower alkylcarbonyl, cyano lower alkenyl, lower alkenylaminocarbonyl, lower alkenylamino thiocarbonyl, substituted lower alkyl(substituent: CN, ═O, and/or ═NH), optionally substituted heterocyclicgroup, optionally substituted carboxy, optionally substitutedcarboxyalkyl, optionally substituted salfamoyl, and optionallysubstituted salfamoylalkyl.

More Preferred Embodiment

R¹ is optionally substituted aralkyl, preferably optionally substitutedbenzyl. Examples of such substituent include one or more substituentselected from halogen, hydroxy, cyano, nitro, amino, substituted amino(example of substituent: lower alkyl), lower alkyl, lower alkoxy and thelike, preferably halogen. R¹ is more preferably benzyl at leastoptionally substituted with halogen, more preferably 4-F-benzyl.

R² and R³ are each independently hydrogen, optionally substituted alkyl,optionally substituted amino, optionally substituted alkenyl, oroptionally substituted alkoxy. Preferably, R² is hydrogen; and R³ isoptionally substituted alkyl, optionally substituted amino, optionallysubstituted alkenyl, or optionally substituted alkoxy. More preferably,R³ is optionally substituted alkyl, optionally substituted alkenyl oroptionally substituted amino.

Each substituent for “optionally substituted” in the definitions of R²and R³ is a non-cyclic group. Examples of such non-cyclic group is oneor more identical or different group(s) selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkoxy lower alkyl,hydroxy lower alkoxy lower alkyl, hydroxy, hydroxy lower alkyl, amino,substituted amino (e.g., formylamino, lower alkylcarbonylamino, loweralkylamino, lower alkylaminothiocarbonylamino), lower alkylamino loweralkyl, halogen, carboxy, lower alkoxy carbonyl, CN, SO₃H, loweralkylthio, lower alkylthio lower alkyl, hydroxy lower alkylthio, loweralkenyloxy, lower alkylcarbonyl, lower alkoxy carbonyl lower alkyl,hydroxy lower alkoxy, lower alkoxy lower alkoxy, COCONH₂, CSNH₂,thiocarbonyl optionally substituted with lower alkyl, cyano loweralkylcarbonyl, cyano lower alkenyl, formyl, lower alkenylamino carbonyl,lower alkenylaminothiocarbonyl, lower alkenylaminothiocarbonylamino,substituted lower alkyl (example of substituent: CN, ═O, ═NH, OH),carbamoyl optionally substituted with optionally substituted loweralkyl, halogenated lower alkyl, halogenated lower alkoxy, NO₂ and thelike.

More preferably, R² is hydrogen, R³ is optionally substituted alkyl,optionally substituted alkenyl or optionally substituted amino. R³ ispreferably lower alkyl (preferably C1 to C6, more preferably C2 to C4alkyl) optionally substituted with a substituent selected from the groupconsisting of lower alkoxy (e.g., OCH₃), CN, amino optionallysubstituted with mono or di lower alkyl(e.g., NHCH₃, N(CH₃)₂), OH,carboxy, and lower alkoxycarbonyl (e.g., COOCH₃). More preferably,CH₂CH₂OCH₃, CH₂CH₂OEt, CH₂CH₂COOCH₃, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂O(i-Pr),N(CH₃)₂, CH₂CH₂CN, CH₂CH₂N(CH₃)₂, CH₂CH₂N(i-Pr)₂, CH₂CH₂CH₂N(CH₃)₂,CH₂CH₂CH₂N(Et)₂, CH(CH₃)CH₂OH, CH(CH₃)COOCH₃ or CH₂CH(OH)CH₂CH₃. The“optionally substituted amino” is preferably amino substituted with oneor two lower alkyl (e.g., N(CH₃)₂).

R⁴ is hydrogen, optionally substituted carboxy, optionally substitutedformylamino, optionally substituted carbamoyl, optionally substitutedamino (provided that a substituent on amino in “optionally substitutedformylamino”, “optionally substituted carbamoyl” and “optionallysubstituted amino” may form an optionally-substituted N-atom containingheterocyclic ring together with an adjacent N atom), optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

Each substituent for “optionally substituted” in R⁴ may be any ofnon-cyclic group, cyclic group, optionally substituted aryloxy,optionally substituted aryloxy lower alkylcarbonyl, optionallysubstituted arylcarbonyl, and optionally substituted heteroarylcarbonyl.Examples of the cyclic group include optionally substituted saturated orunsaturated carbon ring or heterocyclic ring (e.g., aryl (e.g., phenyl)or heteroaryl). Examples of non-cyclic group include one or twoidentical or different group(s) selected from the group consisting oflower alkyl, lower alkoxy, lower alkoxy lower alkyl, hydroxy loweralkoxy lower alkyl, hydroxy, hydroxy lower alkyl, amino, substitutedamino (e.g., formylamino, lower alkylcarbonylamino, lower alkylamino,lower alkylamino thiocarbonylamino), lower alkylamino lower alkyl,halogen, carboxy, lower alkoxy carbonyl, CN, SO₃H, lower alkylthio,lower alkylthio lower alkyl, hydroxy lower alkylthio, lower alkenyloxy,lower alkylcarbonyl, lower alkoxy carbonyl lower alkyl, hydroxy loweralkoxy, lower alkoxy lower alkoxy, COCONH₂, CSNH₂, thiocarbonyloptionally substituted with lower alkyl, cyano lower alkylcarbonyl,cyano lower alkenyl, formyl, lower alkenylaminocarbonyl, loweralkenylaminothiocarbonyl, lower alkenylaminothiocarbonylamino,substituted lower alkyl (example of substituent: CN, ═O, ═NH, OH),carbamoyl optionally substituted with optionally substituted loweralkyl, halogenated lower alkyl, halogenated lower alkoxy, NO₂ and thelike.

R⁴ is preferably optionally substituted carboxy, optionally substitutedformylamino, optionally substituted carbamoyl (provided that,substituent on amino may form an optionally-substituted N-atomcontaining heterocyclic ring together with an adjacent N atom),optionally substituted alkyl, optionally substituted alkenyl oroptionally substituted heteroaryl.

R⁴ is more preferably optionally substituted formylamino, optionallysubstituted carbamoyl (provided that a substituent on amino may form anoptionally-substituted N-atom containing heterocyclic ring together withan adjacent N atom), optionally substituted alkyl, or optionallysubstituted alkenyl.

The term “optionally substituted carboxy” in R⁴ means —COOR (R ishydrogen or substituent), and the R is preferably lower alkyl (e.g.,CH₃), hydroxy lower alkyl (e.g., CH₂CH₂OH), lower alkoxy lower alkyl(e.g., CH₂CH₂OCH₃), optionally substituted amino lower alkyl (example ofsubstituent: lower alkanoyl (e.g., acetyl); specific example:CH₂CH₂NHCOCH₃), or optionally substituted heterocyclic group (e.g.,optionally substituted piperidyl (example of substituent: loweralkylcarbonyl (e.g., acetyl), lower alkylsulfonyl (e.g.,methanesulfonyl))).

The term “optionally substituted formylamino” in R⁴ means “—NHCOH” whoseone or two hydrogen is optionally substituted, and the substituent isselected from lower alkyl (e.g., CH₃), hydroxy lower alkyl (e.g.,CH₂CH(OH)CH₃), lower alkoxy lower alkyl (e.g., CH₂OCH₃), optionallysubstituted carbamoyl lower alkyl (example of substituent: lower alkyl;specific example: CH₂CH₂CON(CH₃)₂), optionally substituted lower alkoxy(e.g., OCH₃), optionally substituted amino (e.g., N(CH₃)₂), optionallysubstituted heterocyclic group (e.g., furan, tetrahydrofuran), loweralkoxy carbonyl lower alkyl (e.g., CH(CH₃)COOCH₃), and optionallysubstituted carbamoyl (example of substituent: lower alkoxy (e.g.,OCH₃), lower alkyl (e.g., CH₃), and lower alkylamino (e.g. N(CH₃)₂),lower alkoxy lower alkyl).

The substituent for “optionally substituted carbamoyl” in R⁴ ispreferably 1) lower alkyl (e.g., CH₃, CH(CH₃)₂), 2) optionallysubstituted lower alkyl (substituent: hydroxy, lower alkoxy (e.g.,OCH₃), halogen, cyano, optionally substituted amino (e.g., NHMe),optionally substituted lower alkoxy, carbamoyl, aryloxy), 3) cycloalkyl,4) cycloalkyl lower alkyl, 5) optionally substituted heterocyclic group(substituent: halogen, OH, lower alkyl, lower alkoxy, amino, loweralkylamino, oxo; heterocyclic, for example, thiophene, pyrazolidine,morpholino, furan, tetrahydrofuran, piperidine, thiazole, pyrrolidine),6) optionally substituted heterocyclic group lower alkyl (substituent:halogen, OH, lower alkyl, lower alkoxy, amino, lower alkylamino, oxo;heterocyclic, for example, those as same as the above 5), 7) optionallysubstituted aryl (example of substituent: halogen, OH, lower alkyl,lower alkoxy, amino, lower alkylamino), 8) optionally substitutedaryloxy lower alkyl (example of substituent: halogen, OH, lower alkyl,lower alkoxy, amino, lower alkylamino), 9) optionally substitutedaralkyl (example of substituent: halogen, OH, lower alkyl, lower alkoxy,amino, lower alkylamino), 10) optionally substituted carbamoyl loweralkyl (e.g., CH₂CON(CH₃)₂), 11) optionally substituted lower alkoxy(e.g., OCH₃), 12) optionally substituted amino (e.g., N(CH₃)₂, NHCOCH₃,NHCH₂CH₂OH), 13) optionally substituted alkenyl, or 14) optionallysubstituted alkynyl (e.g., CH₂C═CH).

Preferably, examples of the substituent for “optionally substitutedamino” in R⁴ include lower alkyl (e.g., CH₂CH₃), hydroxy lower alkyl,lower alkoxy lower alkyl (e.g., CH₂CH₂OCH₃), optionally substitutedheterocyclic group, and optionally substituted carbamoyl lower alkyl.

The substituent for “optionally substituted alkyl” or “optionallysubstituted alkenyl” in R⁴ is preferably hydroxy, halogen, optionallysubstituted heterocyclic group (e.g., morpholino), optionallysubstituted lower alkoxy (e.g., OCH₃), optionally substituted amino(example of substituent: lower alkyl, lower alkylcarbonyl (e.g.,COCH₃)), optionally substituted carbamoyl, or optionally substitutedcarboxy (e.g., lower alkoxy carbonyl), and more preferably, hydroxy orlower alkoxy (e.g., OCH₃).

The substituent for “optionally substituted aryl” or “optionallysubstituted heteroaryl” in R⁴ is preferably hydroxy, lower alkyl,hydroxy lower alkyl, lower alkoxy lower alkyl, optionally substitutedaminoalkyl, optionally substituted carbamoyl lower alkyl, optionallysubstituted lower alkoxy, optionally substituted amino (e.g., NHMs),optionally substituted carbamoyl (e.g., CON(CH₃)₂), optionallysubstituted alkenyl, optionally substituted carboxy, optionallysubstituted carboxyalkyl, optionally substituted salfamoyl (e.g.,SO₂NH₂), or optionally substituted salfamoylalkyl.

The substituent on amino in the above “optionally substitutedformylamino”, “optionally substituted amino” or “optionally substitutedcarbamoyl” may form an optionally-substituted N-atom containingheterocyclic ring together with an adjacent N atom. Such an N-atomcontaining heterocyclic ring is preferably 5 to 8-membered aromatic ringor aliphatic ring, and the ring may further intervened by N, O, S, SO₂and the like. More preferably, morpholine and piperazine areexemplified. The heterocyclic ring may be optionally substituted withoxo, lower alkyl (e.g., methyl) and the like.

More preferably, R⁴ is, for example, groups shown below or substituentscorresponding to R⁴ in each compound described in Example B-30.

In compound (I), R¹ is preferably optionally substituted aralkyl, morepreferably optionally substituted benzyl, particularly preferably benzyloptionally substituted with at least halogen (e.g., 4-F-benzyl); R² ishydrogen; R³ is lower alkyl (preferably C1 to C6, more preferably C2 toC4 alkyl) which is optionally substituted with a substituent selectedfrom a group consisting of optionally substituted alkyl, optionallysubstituted amino, optionally substituted alkenyl, or optionallysubstituted alkoxy, more preferably lower alkoxy (e.g., OCH₃), CN, aminooptionally substituted with mono- or di-lower alkyl (e.g., NHCH₃,N(CH₃)₂), OH, carboxy, and lower alkoxy carbonyl(e.g., COOCH₃), and eachsubstituent for “optionally substituted” in R³ is preferably theaforementioned non-cyclic group, R³ is more preferably CH₂CH₂OCH₃,CH₂CH₂OEt, CH₂CH₂COOCH₃, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂O(i-Pr), N(CH₃)₂,CH₂CH₂CN, CH₂CH₂N(CH₃)₂, CH₂CH₂N(i-Pr)₂, CH₂CH₂CH₂N(CH₃)₂,CH₂CH₂CH₂N(Et)₂, CH(CH₃)CH₂OH, CH(CH₃)COOCH₃ or CH₂CH(OH)CH₂CH₃; R⁴ ispreferably optionally substituted carboxy, optionally substitutedformylamino, optionally substituted carbamoyl (provided that thesubstituent on amino may form an optionally-substituted N-atomcontaining heterocyclic ring together with an adjacent N atom),optionally substituted alkyl, optionally substituted alkenyl oroptionally substituted heteroaryl.

The present invention also provides a pharmaceutically acceptable saltof Compound (I) and solvates thereof. All of the theoretical possibletautomers and geometrical isomers of a compound of the present inventionare also within the scope of the present invention.

Pharmaceutically acceptable salts of a compound of the present inventioninclude, as basic salts, for example, alkali metal salts such as sodiumor potassium salts; alkaline-earth metal salts such as calcium ormagnesium salts; ammonium salts; aliphatic amine salts such astrimethylamine, triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine, brocaine, meglumine, diethanolamine orethylenediamine salts; aralkyl amine salts such asN,N-dibenzylethylenediamine or benethamine salts; heterocyclic aromaticamine salts such as pyridine salts, picoline salts, quinoline salts orisoquinoline salts; quaternary ammonium salts such astetramethylammonium salts, tetraethylammonium salts,benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts ortetrabutylammonium salts; and basic amino acid salts such as argininesalts or lysine salts. Acid salts include, for example, inorganic acidsalts such as hydrochloride, sulfates salts, nitrate salts, phosphatessalts, carbonates salts, hydrogencarbonates or perchlorate; organic acidsalts such as acetates, propionates, lactates, maleates, fumarates,tartaric acid salts, malates, citrates salts, or ascorbates; sulfonatessuch as methanesulfonates, isethionates, benzenesulfonates, orp-toluenesulfonates; and acidic amino acid salts such as aspartates orglutamates.

As a solvate of compound of the present invention, alcoholate, hydrateand the like are exemplified.

Representative general production process of compounds of the presentinvention will be explained below. Preferably,8-hydroxy-1,6-naphthyridine scaffold is constructed in accordance withor following the method described in Example A-1 below. Then accordingto methods well-known by ones skilled in the art, modification of5-position or 7-position in side chains, or deprotection of a protectinggroup of hydroxyl group at 8-position may be conducted.

-   (1) Formation of amide group at 7-position

(R is hydrogen or hydroxy protecting group; R^(4′) is R⁴ or leavinggroup (e.g., halogen))

Compound (I-3) is amidated to produce Compound (I-2). This step may bepreferably conducted by allowing amines (HNR²R³) to react in a solventin the presence of a condensing agent.

As the condensing agent, dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the likemay be used. If necessary, 1-hydroxybenzotriazole, N-hydroxysuccinimideor the like reagent may be added.

The reaction may be conducted at a temperature ranging from 0 to 100°C., preferably from 20 to 30° C.

As the reaction solvent, a wide variety of aprotic solvents may be used,and tetrahydrofuran, N,N-dimethylformamide, dichloromethane and the likeare preferred.

In the above reaction, when the R^(4′) moiety is a leaving group such ashalogen, the leaving group may be converted to R⁴ such as carboxy,carboxy ester, substituted amino in accordance with the method oflater-described (3) after amidation of 7-position.

-   (2) Deprotection of protecting group of hydroxyl group at 8-position

(R is hydroxy protecting group)

Compound (I-2) is deprotected to produce Compound (I).

This step may be conducted by heating in a reaction solvent in thepresence of trialkylsilyl halide and alkaline metal iodide.

As the trialkylsilyl halide, trimethylsilyl chloride and the like may beused.

As the alkaline metal iodide, for example, NaI or KI may be used.

The reaction may be conducted at a temperature ranging from roomtemperature to 100° C., preferably 70 to 90° C.

As the reaction solvent, a polar solvent such as acetonitrile ispreferably used.

This step may be conducted using hydrogen bromide/acetic acid and underheating.

As the hydrogen bromide/acetic acid, 47% hydrogen bromide/acetic acid ispreferably used.

This step may further be conducted by using BBr₃ at a temperatureranging form 0° C. to room temperature, or using pyridinium chloride at150 to 220° C. Deprotection may be conducted by treating withtrifluoroacetic acid.

-   (3) Introduction of substituted amino group in 5-position

-   (Step 1)

Compound (I-4) is caused to react with halogen (e.g., bromine)preferably in acetic acid solvent in the presence of sodium acetate orthe like, to give Compound (I-5). The reaction temperature is usuallyabout 0° C. to 100° C., preferably about 20° C. to 30° C.

-   (Step 2)

Compound (I-5) is subjected to carbon monoxide introducing reaction togive Compound (I-7). Preferably, Compound (I-5) is caused to react withcarbon monoxide in a solvent such as dimethyl sulfoxide in the presenceof palladium acetate (II), 1,3-bis(diphenylphosphino)propane,triethylamine, and water. The reaction temperature is usually from roomtemperature to 100° C., preferably room temperature.

-   (Step 3)

Compound (I-5) is subjected to carbon monoxide introducing reactionsimilarly to Step 2, to produce Compound (I-6). In this case, alcoholhaving a R′ moiety may coexist.

-   (Step 4)

Compound (I-7) is treated with diphenylphosphoryl azide and triethylamine preferably in a solvent such as dimethylformamide, to giveCompound (I-8). The reaction temperature is usually about 70° C. to 80°C.

-   (Step 5)

Compound (I-8) is N-alkylated, N-acylated, or N-sulfonylated, to giveCompound (I-9). The reaction temperature is usually from about 0° C. to100° C., preferably from about 0° C. to room temperature. Compound (I-9)may also be obtained by amidation of Compound (I-7).

Examples of hydroxy protecting group represented by “R” include C1 to C8alkyls (methyl, methoxymethyl, ethyl, ethoxymethyl, iodoethyl, propyl,isopropyl, butyl, isobutyl, ethoxyethyl, methylthioethyl,methanesulfonyl ethyl, trichloroethyl, t-butyl etc.), C3 to C8 alkenyls(propenyl, allyl, isoprenyl, hexenyl, phenylpropenyl, dimethylhexenyletc.), C7 to C19 aralkyls (benzyl, methylbenzyl, dimethylbenzyl,methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl,phenylethyl, trityl, di-t-butylhydroxybenzyl, phthalidyl, phenacyletc.), C6 to C12 aryls (phenyl, toluoyl, diisopropylphenyl, xylyl,trichlorophenyl, pentachlorophenyl, indanyl etc.), C1 to C12 aminogroups (groups that form esters with acetone oxime, acetophenone oxime,acetoaldoxime, N-hydroxysuccinic imide, N-hydroxyphthalimide and thelike), C3 to C12 hydrocarbonated silyls (trimethylsilyl,dimethylmethoxysilyl, t-butyldimethylsilyl etc.), C3 to C12hydrocarbonated stanyls (trimethylstanyl etc.).

Compounds of the present invention obtained by the above methods mayfurther be chemically modified by methods that are well known by oneshaving originally skill in the art. As a starting material for eachreaction, a salt or reactive derivative may be used as desired. When afunctional group exists (e.g., amino, hydroxy, carboxy) in eachreaction, it may be protected in advance.

The compound of the present invention is useful as a pharmaceuticalcomposition such as an antiviral agent. The compound of the presentinvention has an outstanding inhibitory activity against integrase ofviruses. Therefore, the compound of the present invention is expected toprevent or treat various diseases caused by viruses producing at leastintegrase to grow in animal bells upon infection, and is useful as, forexample, an integrase inhibitor against retroviruses (e.g., HIV-1,HIV-2, HTLV-1, SIV or FIV), especially, an anti-HIV agent.

The compound of the present invention can be used in a combinationtherapy with an anti-HIV agent possessing other inhibitory mechanismsuch as a reverse transcriptase inhibitory agent and/or a proteaseinhibitory agent. Since any integrase inhibitor has not been on saleyet, it is useful to use the compound of the present invention incombination therapy with a reverse transcriptase inhibitory agent and/ora protease inhibitory agent.

And the compound of the present invention can be used not only as ananti-HIV mixture but also as a concomitant agent enhancing the anti-HIVactivity of the other anti-HIV agent such as in a cocktail therapy.

The compound of the present invention can be used so as in the genetherapy using a retrovirus vector derived from HIV or MLV to suppressthe spread of the retrovirus vector infection over non-target tissues.Especially, in the case that cells infected with such a vector in vitroare put back in a body, a previous administration of the compound of thepresent invention prevents an unnecessary infection inside the body.

The compounds of the present invention can be administered orally orparenterally. For oral administration, the compounds of the presentinvention can be used in any form of usual formulations, for example,solid formulations such as tablets, powders, granules, capsules; aqueousformulations; oleaginous suspensions; or solutions such as syrup orelixir. For parenteral administration, the compounds of the presentinvention can be used as an aqueous or oleaginous suspension injection,or nose drops. In the preparation of such formulations, conventionalexcipients, binding agents, lubricants, aqueous solvents, oleaginoussolvents, emulsifying agents, suspending agents, preservatives orstabilizers can be optionally used. And as an anti-HIV agent, oralagents are especially preferable.

The formulation according to the present invention may be manufacturedby combining (for example, admixing) a curatively effective amount of acompound of the present invention with a pharmaceutically acceptablecarrier or diluent. The formulation of the present invention may bemanufactured with well-known and easily available ingredients inaccordance with a known method.

In the case of manufacturing a pharmaceutical composition according tothe present invention, an active ingredient is admixed or diluted with acarrier, or they are contained in a carrier in the form of capsule,sacheier, paper, or another container. In the case of a carrierfunctioning as a diluent, the carrier is a solid, semi-solid, or liquidmaterial, which functions as a medium. Accordingly, a formulationaccording to the present invention may be produced in the form oftablet, pill, powder medicine, intraoral medicine, elixir agent,suspending agent, emulsifier, dissolving agent, syrup agent, aerosolagent (solid in liquid medium), and ointment. Such a formulation maycontain up to 10% of an active compound. It is preferred to formulate acompound of the present invention prior to administration.

Any suitable carrier well known to those skilled in the art may be usedfor the formulation. In such formulation, a carrier is in the form ofsolid, liquid or a mixture thereof. For instance, a compound of thepresent invention is dissolved into 4% dextrose/0.5% sodium citrateaqueous solution so as to be 2 mg/ml concentration for intravenousinjection. Solid formulation includes powder, tablet, and capsule. Solidcarrier consists of one or more of material(s) for serving also asfragrant, lubricant, dissolving agent, suspension, binder, tabletdisintegrator or capsule. A tablet for oral administration contains asuitable excipient such as calcium carbonate, sodium carbonate andlactose, calcium phosphate together with a disintegrator such as cornstarch and alginic acid and/or a binder such as gelatin and acacia, anda lubricant such as magnesium stearate, stearic acid and talc.

In a powder medicine, a carrier is a finely pulverized solid, which isblended with finely pulverized active ingredients. In a tablet, activeingredients are admixed with a carrier having required binding power ina suitable ratio, and it is solidified in a desired shape and size.Powder medicine and tablet contain as the active ingredient about 1 toabout 99% by weight of novel compounds of the present invention. Exampleof suitable solid carriers include magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth gum, methyl cellulose, sodium carboxymethylcellulose,low-melting wax, and cocoa butter.

A liquid formulation contains suspending agent, emulsifier, syrup agentor elixir agent. Active ingredients may be dissolved or suspended into apharmaceutically acceptable carrier such as sterile water, a sterileorganic solvent or a mixture thereof. Active ingredients may bedissolved frequently into a suitable organic solvent such as propyleneglycol aqueous solution. When finely pulverized active ingredients aredispersed into aqueous starch, sodium carboxylmethylcellulose solutionor suitable oil, the other compositions can be prepared.

Although an appropriate dosage of the compound of the present inventionvaries depending on the administration route, age, body weight,conditions of the patient, and kind of disease, in the case of oraladministration, the daily dosage for an adult can be usually betweenapproximately 0.05-3000 mg, preferably approximately 0.1-1000 mg, ifnecessary, in divisions. In the case of parenteral administration, thedaily dosage for an adult can be between approximately 0.01-1000 mg,preferably approximately 0.05-500 mg.

EXAMPLES Abbreviations

Me=methyl; Bn=benzyl; Bz=benzoyl; Boc=tert-butoxycarbonyl;Cbz=benzyloxycarbonyl; DMSO=dimethylsulfoxide

Example A-1

A-1. Methyl 3-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-carbonate

1) According to the method reported in Document (Chem. Commun., 1984,1287), 4-fluoroiodobenzene (50 g, 225 mmol) and allyl alcohol (23 ml,337 mmol) were subjected to Heck reaction in the presence of palladiumacetate, which were then distilled under reduced pressure (94-96° C., 7mmHg), to give 3-(4-fluorophenyl)propional 2 (27.5 g) in 80% yield.

NMR (CDCl₃) d: 2.73-2.79 (2H, m), 2.93 (2H, t, J=7.4 Hz), 6.94-7.00 (2H,m), 7.12-7.17 (2H, m), 9.81 (1H, t, J=1.2 Hz).

2) The above compound 2 (53 g, 348 mmol) was heated for 1 hour at 110°C. in 37% formalin (31.2 ml) and diethylamine hydrochloride (38.3 g),and added with ether and washed three times. After drying over anhydrousmagnesium sulfate, distillation under reduced pressure (101-103° C., 8mmHg) was conducted to give 2-(4-fluorobenzyl)-2-propenal 3 (45.3 g) in79% yield.

NMR (CDCl₃) d: 3.54 (2H, s), 6.07 (1H, d, J=0.6 Hz), 6.11 (1H, t, J=1.4Hz), 6.94-7.01 (2H, m), 7.11-7.16 (2H, m), 9.59 (1H, s).

3) According to the method reported in Document (JP-A 64-16764), aftercausing the above Compound 3 (253 g, 1.54 mol) and 2-aminobutanedicarboxylic acid diethylester (240 g, 1.28 mol) which is known inDocument (Chem. Pharm. Bull., 1989, 37, 3236.) to react, sodiumhydroxide (154 g, 3.85 mol) aqueous solution (600 ml) was added foralkaline hydrolysis, to give 2-(4-fluorobenzyl)pyridine-2,3-dicarboxylicacid 4 (150 g) in 43% yield.

NMR (DMSO-d₆) d: 4.09 (2H, s), 7.11-7.18 (2H, m), 7.32-7.38 (2H, m),8.05 (1H, d, J=2.0 Hz), 8.68 (1H, d, J=2.0 Hz), 13.50 (2H, br s).

4) After heating the above Compound 4 (120 g, 466 mmol) for 2 hours at120° C. in acetic anhydride, the solvent was distilled off, and theresultant acid anhydride was subjected to isopropyl-added alcoholysis,followed by reduction of the acid chloride according to the methodreported in Document (J. Med. Chem., 1989, 32, 827.), to give5-(4-fluorobenzyl)-3-hydroxymethylpyridine-2-carboxylic acid isopropylester 5 (32.1 g) in 35% yield.

NMR (CDCl₃) d: 1.45 (6H, d, J=6.2 Hz), 3.63 (1H, br s), 4.01 (2H, s),4.76 (2H, s), 5.34 (1H, sep, J=6.2 Hz), 6.69-7.03 (2H, m), 7.00-7.15(2H, m), 7.61 (1H, d, J=2.1 Hz), 8.54 (1H, d, J=2.1 Hz).

5) After subjecting the above Compound 5 (59.0 g, 195 mmol) to Mitsunobureaction with N-tosylglycine methyl ester according to the methoddescribed in Document (WO02/30930), ring-closure was caused with 1Msodium methoxide, to give3-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methylester 6 (50.3 g) in 83% yield.

NMR (CDCl₃) d: 4.13 (3H, s), 4.23 (2H, s), 7.02-7.08 (2H, m), 7.17-7.23(2H, m), 7.97 (1H, m), 8.77 (1H, s), 9.08 (1H, d, J=2.1 Hz), 11.77 (1H,s).

6) To a dimethylformamide solution (200 ml) of the above Compound 6(3.56 g, 11.4 mmol) was added N-iodo succinimide (3.06 g, 13.6 mmol),and the solution was stirred overnight at room temperature. The reactionsolution was distilled off under reduced pressure, and the residue wasadded with chloroform, washed with 10% sodium hydrogen sulfite aqueoussolution and water, and dried over anhydrous sodium sulfate, and thenthe solvent was distilled off. Precipitated crystals were collected byfiltering, and washed with methanol to give3-(4-fluorobenzyl)-8-hydroxy-5-iodo[1,6]naphthyridine-7-carboxylic acidmethyl ester 7 (4.97 g) in 99% yield.

NMR (CDCl₃) d: 4.10 (3H, s), 4.27 (2H, s), 7.03-7.09 (2H, m), 7.18-7.23(2H, m), 8.10 (1H, m), 8.99 (1H, d, J=1.8 Hz), 11.76 (1H, s).

7) To a dimethylformamide suspension (80 ml) of the above Compound 7(8.76 g, 20 mmol) were added DBU (4.48 ml, 30 mmol) and benzylbromide(3.56 ml, 30 mmol), and the solution was stirred for 5 hours at roomtemperature. The reaction solution was added with 0.5M citric acidaqueous solution and 10% sodium hydrogen sulfite aqueous solution, andextracted twice with ethyl acetate. The organic phase was washed withwater, saturated sodium hydrogen carbonate and saturated brine. Afterdrying over anhydrous magnesium sulfate, the residue obtained bydistilling off the solvent was subjected to silica gel chromatography.The precipitated crystals were collected by filtering, and washed withdiisopropyl ether, to give8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylicacid methyl ester 8 (7.64 g) in 72% yield.

NMR (CDCl₃) d: 3.94 (3H, s), 4.26 (2H, s), 5.54 (2H, s), 7.03-7.09 (2H,m), 7.19-7.26 (2H, m), 7.32-7.41 (3H, m), 7.55-7.57 (2H, m), 8.13 (1H,m), 8.97 (1H, d, J=2.1 Hz).

8) To the above Compound 8 (20.0 g, 37.86 mmol) was addedtetrahydrofuran (100 ml) and methanol (100 ml) to give suspension,followed by addition of 2N sodium hydroxide aqueous solution (24.6 ml,49.2 mmol) under stirring at room temperature and stirring wascontinued. After 4 hours, 2N hydrochloric acid (24.6 ml, 49.2 mmol) wasadded, and the reaction solution was concentrated under reduced pressureand added with chloroform (150 ml) and water (150 ml). Then the solutionwas shaken for separation, washed with saturated sodium hydrogencarbonate and dried over sodium sulfate, followed by distillation underreduced pressure. The residue (20.8 g) was added with diisopropyl ether(80 ml) and n-hexane (80 ml), warmed on a water bath forcrystallization, and then the crystals were collected by filtering andwashed with diisopropyl ether:n-hexane (1:1), to give8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylicacid 9 in a yield of (19.41 g, 99.7%).

Melting point: 132-134° C.

NMR (CDCl₃) d: 4.28 (2H, s), 5.69 (2H, s), 7.05-7.11 (2H, m), 7.20-7.26(2H, m), 7.31-7.39 (3H, m), 7.59-7.62 (2H, m), 8.13-8.14 (1H, m), 9.03(1H, d, J=2.1 Hz), 10.80 (1H, brs).

9) To the above Compound 9 (7.0 g, 13.6 mmol), 1-hydroxybenzotriazole(208 mg, 1.36 mmol) was added dichloromethane (75 ml) to givesuspension, and was added 2-methoxyethyl amine (1.42 ml, 16.3 mmol) innitrogen gas flow under stirring on ice, followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.13 g,16.3 mmol). 30 minutes later, the solution was stirred at roomtemperature. After 3 hours, the reaction solution was subjected todistillation under reduced pressure, and to the residue (12 g) was addedand solved ethyl acetate (150 ml) and water (100 ml), and followed by 2Nhydrochloric acid aqueous solution (5.7 ml, 11.4 mmol). Then thesolution was shaken for separation, washed once with water and withsodium chloride aqueous solution, dried over sodium sulfate andsubjected to distillation under reduced pressure. The resultant residue(7.97 g) was solved in methanol (5 ml), and added with diisopropyl ether(35 ml) little by little under warming and left at room temperature.Then the product was collected by filtering and washed with diisopropylether, to give Compound 10 (6.31 g, 81.1%). The filtrate was subjectedto silica gel silica gel chromatography, to give8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide 10 (437 mg, 5.6%).

NMR (CDCl₃) d: 3.38 (3H, s), 3.56-3.59 (2H, m), 3.64-3.70 (2H, m), 4.25(2H, s), 5.52 (2H, s), 7.03-7.10 (2H, m), 7.19-7.24 (2H, m), 7.31-7.39(3H, m), 7.64-7.66 (2H, m), 7.98 (1H, m), 8.09-8.10 (1H, m), 8.97 (1H,d, J=2.1 Hz).

10) The above Compound 10 (400 mg, 0.7 mmol) and palladium acetate (8mg, 0.035 mmol) were solved in dimethylformamide (11 ml), added withmethanol (0.29 ml, 7.16 mmol) followed by triethylamine (0.30 ml, 2.15mmol), and deaeration of the reaction vessel with carbon monoxide wasrepeated three times. Then the solution was stirred at room temperaturein the presence of carbon monoxide. After 6 hours, the reaction mixturewas added with ethyl acetate (40 ml), water (30 ml), an 10% citric acid(4 ml), and shaken for separation. Then the aqueous phase was extractedonce with ethyl acetate, and the ethyl acetate phase was washed twicewith water, dried over sodium sulfate and subjected to distillationunder reduced pressure. The obtained residue (0.38 g) was subjected tosilica gel chromatography, to give crystalline8-benzyloxy-3-(4-fluorobenzyl)-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-carboxylicacid methyl ester 11 (296 mg, 84.1%).

Melting point: 94° C.

NMR (CDCl₃) d: 3.373H, s), 3.56-3.59 (2H, m), 3.65-3.71 (2H, m), 4.04(3H, s), 4.22 (2H, s), 5.67 (2H, s), 7.01-7.07 (2H, m), 7.19-7.24 (2H,m), 7.30-7.39 (3H, m), 7.61-7.64 (2H, m), 8.08 (1H, m), 9.03 (1H, d,J=2.1 Hz), 9.10 (1H, m).

11) To the above Compound 11 (293 mg, 0.583 mmol) was added and solvedtrifluoroacetic acid (2.9 ml), and the solution was left at roomtemperature. After 1.5 hours, the reaction solution was distilled underreduced pressure, and the residue was added with toluene and distilledagain. To the resultant residue was added and solved chloroform, and thesolution was injected into ice water, and a saturated sodium hydrogencarbonate aqueous solution (2 ml) was added and shaken, and then pH wasadjusted to 8.60. Thereafter, the solution was added with 10% citricacid aqueous solution (2.5 ml), shaken, and separated after adjusting pHto 5.36, and then washed once with water. After drying over sodiumsulfate, the residue obtained by distillation under reduced pressure wasrecrystallized from acetone-diethyl ether, to give Compound A-1 (174 mg,72.5%).

Melting point: 168-169° C.

Elemental analysis for C₂₁H₂₀FN₃O₅

Calcd.(%): C, 61.01; H, 4.88; F, 4.60; N, 10.16.

Found.(%): C, 61.15; H, 4.76; F, 4.44; N, 10.26.

NMR (CDCl₃) d: 3.44 (3H, s), 3.62-3.66 (2H, m), 3.70-3.76 (2H, m), 4.02(3H, s), 4.22 (2H, s), 7.00-7.06 (2H, m), 7.17-7.22 (2H, m), 8.34 (1H,m), 9.02 (1H, d, J=2.1 Hz), 9.11 (1H, d, J=2.1 Hz), 13.88 (1H, brs).

Example A-2

A-25-acetylamino-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxylicacid 2-methoxyethyl amide

1) To Compound 10 (571 mg, 1 mmol) and acetic acid amide (89 mg, 1.5mmol) was added and solved dioxane (12 ml), and were added cesiumcarbonate (48.8 mg, 1.5 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxancene (88 mg, 0.152 mmol), andpalladium acetate (24 mg, 0.107 mmol) under stirring at room temperaturein nitrogen gas flow, and then the solution was stirred for 5 hoursunder heating in an oil bath at 70° C. The mixture was added with ethylacetate, water and ammonium chloride aqueous solution for extraction,washed with sodium chloride aqueous solution, dried over sodium sulfateand the subjected to distillation. The obtained residue was subjected tosilica gel chromatography and recrystallized from acetone-diisopropylether, to give5-acetylamino-8-benzyloxy-3-(4-fluorobenzyl)[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl) amide 12 (245 mg, 80.9%) as colorless crystals.

Melting point: 147-149° C.

NMR (CDCl₃) d: 2.31 (3H, brs), 3.28 (3H, s), 3.46 (2H, t, J=5.1 Hz),3.58 (2H, t, J=5.1 Hz), 4.21 (2H, s), 5.53 (2H, s), 7.00-7.06 (2H, m),7.19-7.23 (2H, m), 7.36-7.39 (3H, m), 7.57-7.59 (2H, m), 8.12 (1H, brs),8.20 (1H, m), 8.46 (1H, brs), 9.00 (1H, d, J=1.8 Hz).

2) According to the method of 11) in Example A-1, A-2 (271 mg) wasobtained from the above Compound 10 (390 mg, 0.776 mmol) in 85% yield.

Melting point: 216-217° C.

Elemental analysis for C₂₁H₂₀FN₄O₄

Calcd.(%): C, 61.16; H, 5.13; F, 4.61; N, 13.59.

Found.(%): C, 61.06; H, 5.17; F, 4.38; N, 13.43.

NMR (CDCl₃) d: 2.30 (3H, brs), 3.43 (3H, s), 3.59-3.63 (2H, m),3.66-3.72 (2H, m), 4.20 (2H, s), 6.99-7.05 (2H, m), 7.15-7.20 (2H, m),7.67 (1H, brs), 7.97 (1H, brs), 8.06 (1H, m), 9.00 (1H, d, J=2.1 Hz),13.21 (1H, brs).

Example A-3

A-3N-[3-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′-methyloxalamide

1) According to the method of 10) in Example A-1, from the aboveCompound 8 (30 g, 56.8 mmol), was obtained8-benzyloxy-3-(4-fluorobenzyl)[1,6]naphthyridine-5,7-dicarboxylic acid7-methyl ester 13 (21.1 g) in 83% yield.

NMR (CDCl₃) d: 3.96 (3H, s), 4.26 (2H, s), 5.77 (2H, s), 7.04 (2H, m),7.23 (2H, m), 7.33-7.42 (3H, m), 7.51-7.42 (2H, m), 9.07 (1H, d, J=2.1Hz), 9.74 (1H, m), 11.4 (1H, s).

2) A tetrahydrofuran (95 ml) solution of the above Compound 13 (9.49 g,21.3 mmol), diphenylphosphoryl azide (5.72 ml, 25.5 mmol), triethylamine (4.14 ml, 29.7 mmol) and 2-(trimethylsilyl)ethanol (4.26 ml, 29.7mmol) was refluxed under heating for 3 hours in a nitrogen gas flow.After restoring to room temperature, the reaction solution was addedwith 10% citric acid aqueous solution and ethyl acetate, and extractedthree times with ethyl acetate. The extract was washed with 10% citricacid aqueous solution, saturated sodium hydrogen carbonate aqueoussolution and water. After drying over anhydrous sodium sulfate, andconcentrating under reduced pressure, a crude product of Compound 14 wasobtained as oily substance (14.31 g). This was used for the subsequentreaction without further purification.

3) To a tetrahydrofuran (95 ml) solution of the above crude product ofCompound 14 (14.31 g) were added 1M tetrabutyl ammoniumfluoride-tetrahydrofuran solution (32 ml) and potassium fluoride (1.86g), and the mixture was stirred overnight at room temperature. Thereaction solution was added with 10% citric acid aqueous solution andethyl acetate, and extracted three times with ethyl acetate. The extractwas washed with 10% citric acid aqueous solution, saturated sodiumhydrogen carbonate aqueous solution, water and saturated brine, and thendried over anhydrous sodium sulfate. The residue concentrated underreduced pressure was purified on silica gel chromatography, and thenrecrystallized with ethyl acetate-diisopropyl ether, to give5-amino-8-benzyloxy-3-(4-fluorobenzyl)[1,6]naphthyridine-7-carboxylicacid methyl ester 15 (7.48 g) in 84% yield. Further, 431 mg of secondcrystals were obtained.

Melting point: 159-160° C.

NMR (CDCl₃) d: 3.91 (3H, s), 4.19 (2H, s), 5.28 (2H, br. s), 5.35 (2H,s), 7.03 (2H, t like, J=8.7 Hz), 7.16-7.24 (2H, m), 7.30-7.40 (3H, m),7.56-7.63 (2H, m), 7.86 (1H, br.s), 9.01 (1H, d, J=2.1 Hz).

4) A tetrahydrofuran (20 ml) solution of the above Compound 15 (1.0 g,2.40 mmol) and pyridine (0.49 ml, 6.00 mmol) was cooled to −10° C.,added with oxalyl chloride (0.42 ml, 4.80 mmol) and stirred for 20minutes. At the same temperature, 40% methylamine aqueous solution (1.9ml) was added and stirred for another 10 minutes. The reaction solutionwas added with water and 2M hydrochloric acid and extracted with ethylacetate. The extract was washed with water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified on silica gelchromatography. The obtained solid was washed with methanol, to give8-benzyloxy-3-(4-fluorobenzyl)-5-(methylaminooxalylamino)[1,6]naphthyridine-7-carboxylicacid methyl ester 16 (908 mg) in 75% yield.

NMR (CDCl₃) d: 3.01 (3H, d, J=5.4 Hz), 3.9.4 (3H, s), 4.20 (2H, s), 5.54(2H, s), 7.00-7.06 (2H, m), 7.16-7.22 (2H, m), 7.30-7.45 (3H, m),7.56-7.61 (2H, m), 7.98 (1H, s), 9.03 (1H, d, J=2.1 Hz), 9.81 (1H, brs).

5) The above Compound 16 (388 mg, 0.772 mmol) was dissolved indimethylformamide (5 ml), added with 5M sodium hydroxide aqueoussolution (0.46 ml, 2.30 mmol), and stirred for 4 hours at roomtemperature. To the reaction solution was added 5M hydrochloric acid(0.46 ml, 2.30 mmol) for neutralizing the solution, and then was added 2M hydrochloric acid (0.5 ml) for acidifying the solution. Then water wasadded followed by extraction with chloroform. The extract was washedwith water and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the resultant residue wasrecrystallized with tetrahydrofuran-methanol, to give8-benzyloxy-3-(4-fluorobenzyl)-5-(methylaminooxalylamino)[1,6]naphthyridine-7-carboxylicacid 17 (271 mg) in 72% yield.

NMR (DMSO-d₆) d: 2.78 (3H, d, J=4.9 Hz), 4.26 (2H, s), 5.47 (2H, s),7.11-7.19 (2H, m), 7.35-7.44 (5H, m), 7.56-7.61 (2H, m), 8.30 (1H, s),8.92 (1H, d, J=4.9 Hz), 9.18 (1H, d, J=2.1 Hz), 11.18 (1H, s), 13.44(1H, s).

6) According to the method of 9) in Example A-1, from the above Compound17 (183 mg, 0.375 mmol),N-[8-benzyloxy-3-(4-fluorobenzyl)-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′-methyloxalamide 18 (107 mg) was obtained in 52% yield.

NMR (CDCl₃) d: 3.02 (3H, d, J=5.1 Hz), 3.34 (3H, s), 3.49-3.55 (2H, m),3.61-3.66 (2H, m), 4.20 (1H, s), 5.54 (1H, s), 7.00-7.07 (2H, m),7.16-7.23 (3H, m), 7.43-7.48 (1H, m), 7.61-7.66 (2H, m), 8.06 (1H, s),8.10-8.14 (1H, m), 9.03 (1H, d, J=2.1 Hz).

7) According to the method of 11) in Example A-1, A-3 (64 mg) wasobtained in 77% yield from the above Compound 18 (100 mg, 0.183 mmol).

NMR (DMSO-d₆) d: 2.77 (3H, d, J=4.8 Hz), 3.28 (3H, s), 3.52 (4H, s),4.25 (2H, s), 7.10-7.18 (2H, m), 7.32-7.39 (2H, m), 8.23 (1H, s),8.84-8.95 (2H, m), 9.09 (1H, s), 11.00 (1H, s), 13.71 (1H, s).

Example A-4

A-4 3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-carboxylic acid5-[(3-hydroxypropyl)amide] 7-[(2-methoxyethyl)amide]

1) According to the method 10) in Example A-1, from the above Compound10 (3.00 g, 5.25 mmol),8-benzyloxy-3-(4-fluorobenzyl)-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-carboxylicacid 19 (1.56 g) was obtained in 61% yield.

NMR (CDCl₃) d: 3.29 (3H, s), 13.42-3.50 (2H, m), 3.57-3.64 (2H, m), 4.25(2H, s), 5.79 (2H, s), 7.00-7.08 (2H, m), 7.20-7.26 (2H, m), 7.34-7.43(3H, m), 7.48-7.53 (2H, m), 8.09-8.13 (1H, m), 9.05 (1H, d, J=2.1 Hz),9.74 (1H, d, J=2.1 Hz).

2) According to the method of 9) in Example A-1, from the above Compound19 (200 mg, 0.409 mmol),8-benzyloxy-3-(4-fluorobenzyl)-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-carboxylicacid 3-hydroxypropyl ester 20 (176 mg) was obtained in 77% yield.

NMR (CDCl₃) d: 1.87-1.95 (2H, m), 3.40 (3H, s), 3.57-3.61 (2H, m),3.64-3.73 (4H, m), 3.94 (2H, t, J=5.3 Hz), 4.21 (2H, s), 5.63 (2H, s),6.97-7.06 (2H, m), 7.15-7.26 (2H, m), 7.27-7.39 (3H, m), 7.61-7.66 (2H,m), 8.33 (1H, t, J=5.4 Hz), 9.02 (1H, d, J=2.2 Hz), 9.36-9.40 (1H, m),9.94 (1H, s).

3) According to the method 11) in Example A-1, A-4 (82 mg) was obtainedin 58% yield from the above Compound 20 (170 mg, 0.311 mmol).

NMR (CDCl₃) d: 1.89-1.98 (2H, m), 3.49 (3H, s), 3.62-3.71 (4H, m),3.72-3.79 (2H, m), 4.05 (2H, t, J=5.0 Hz), 4.20 (2H, s), 6.95-7.04 (2H,m), 7.15-7.23 (2H, m), 8.48-8.54 (1H, m), 8.99 (1H, d, J=2.2 Hz), 9.50(1H, br s), 9.90 (1H, d, J=2.2 Hz), 13.40 (1H, s).

Example A-5 to A-8

According to the method of Example A-1, Compounds A-5 to A-8 weresynthesized.

Example A-53-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-carboxylicacid 2-methoxyethyl ester

Melting point: 139-141° C.

Elemental analysis for C₂₃H₂₄FN₃O₆

Calcd.(%): C, 60.39; H, 5.29; F, 4.15; N, 9.19.

Found.(%): C, 60.20; H, 5.21; F, 4.06; N, 9.29.

NMR (CDCl₃) d: 3.44 (3H, s), 3.46 (3H, s), 3.61-3.65 (2H, m), 3.70-3.75(2H, m), 3.78-3.81 (2H, m), 4.21 (2H, s), 4.57-4.60 (2H, m), 6.70-7.06(2H, m), 7.17-7.22 (2H, m), 8.36-8.40 (1H, m), 9.02 (1H, d, J=2.4 Hz),9.08 (1H, d, J=2.4 Hz), 13.88 (1H, brs).

Example A-63-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-carboxylicacid 1-acetylpiperidine-4-yl ester

Melting point: 92-94° C.

Elemental analysis for C₂₇H₂₉FN₄O₆.0.7H₂O

Calcd.(%): C, 60.39; H, 5.29; F, 4.15; N, 9.19.

Found.(%): C, 60.20; H, 5.21; F, 4.06; N, 9.29.

NMR (CDCl₃) d: 1.80-1.95 (2H, m), 1.95-2.10 (2H, m), 2.15 (3H, s), 3.41(3H, s), 3.47-3.54 (1H, m), 3.63-3.75 (6H, m), 3.85-3.91 (1H, m), 4.23(2H, s), 5.32-5.39 (1H, m), 7.01-7.07 (2H, m), 7.18-7.23 (2H, m),8.34-8.38 (1H, m), 9.04 (1H, d, J=2.1 Hz), 9.07 (1H, d, J=2.1 Hz), 13.84(1H, brs).

Example A-77-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-carboxylicacid methyl ester

Melting point: 169-170° C.

Elemental analysis for C₂₀H₁₉FN₄O₄

Calcd.(%): C, 60.39; H, 5.29; F, 4.15; N, 9.19.

Found.(%): C, 60.20; H, 5.21; F, 4.06; N, 9.29.

NMR (CDCl₃) d: 2.82 (6H, s), 4.03 (3H, s), 4.22 (2H, s), 7.00-7.06 (2H,m), 7.17-7.22 (2H, m), 8.77 (1H, brs), 9.03 (1H, d, J=2.1 Hz), 9.07 (1H,d, J=2.1 Hz), 13.60 (1H, brs)

Example A-87-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-carboxylicacid 2-methoxyethyl ester

Melting point: 138 (wet)-210° C.

Elemental analysis for C₂₂H₂₃FN₄O₅

Calcd.(%): C, 60.39; H, 5.29; F, 4.15; N, 9.19.

Found.(%): C, 60.20; H, 5.21; F, 4.06; N, 9.29.

NMR (CDCl₃) d: 2.79 (6H, s), 3.47 (3H, s), 3.78-3.81 (2H, m), 4.21 (2H,s), 4.58-4.61 (2H, m), 7.00-7.06 (2H, m), 7.17-7.22 (2H, m), 8.76 (1H,brs), 9.02 (1H, d, J=2.1 Hz), 9.05 (1H, m), 13.68 (1H, brs).

Example A-9 to A-10

According to the method of Example A-3, Compounds A-9 to A-10 weresynthesized.

A-9.N-[3-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′-methoxyoxalamide

NMR (DMSO-d₆) d: 3.28 (3H, s), 3.52 (4H, s), 3.71 (3H, s), 4.26 (2H, s),7.10-7.18 (2H, m), 7.33-7.38 (2H, m), 8.26 (1H, s), 8.86 (1H, br s),9.10 (1H, d, J=1.8 Hz), 11.11 (1H, s), 12.34 (1H, s), 13.71 (1H, br s).

A-10N-[7-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-yl]-N′-methoxyoxalamide

NMR (DMSO-d₆) d: 2.62 (6H, s), 3.71 (3H, s), 4.25 (2H, s), 7.11-7.18(2H, m), 7.33-7.38 (2H, m), 8.24 (1H, s), 9.09 (1H, d, J=2.1 Hz), 9.83(1H, br s), 11.03 (1H, br s), 12.35 (1H, br s), 13.70 (1H, br s).

A-11N-[7-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-yl]-N′-methyloxalamide

NMR (CDCl₃) d: 2.82 (6H, s), 3.04 (3H, d, J=5.2 Hz), 4.20 (2H, s),6.98-7.07 (2H, m), 7.13-7.21 (2H, m), 7.46-7.54 (1H, m), 7.93 (1H, d,J=1.8 Hz), 8.61 (1H, br s), 9.03 (1H, d, J=1.8 Hz), 9.66 (1H, s), 12.95(1H, br s).

A-122-(N′,N′-dimethylhydrazino)-N-[7-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-yl]-2-oxoacetamide

NMR (CDCl₃) d: 2.73 (6H, s), 2.78 (6H, s), 4.21 (2H, s), 6.99-7.07 (2H,m), 7.13-7.21 (2H, m), 7.88 (1H, d, J=2.0 Hz), 8.10 (1H, br s), 8.47(1H, s), 9.04 (1H, d, J=2.0 Hz), 9.61 (1H, s), 13.11 (1H, br s).

A-13.N-[3-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′-(2-methoxyethyl)oxalamide

NMR (CDCl₃) d: 3.42 (3H, s), 3.44 (3H, s), 3.55-3.65 (6H, m), 3.65-3.73(2H, m), 4.21 (2H, s), 6.98-7.07 (2H, m), 7.13-7.21 (2H, m), 7.72-7.79(1H, m), 7.94 (1H, d, J=2.1 Hz) 8.05-8.12 (1H, m), 9.03 (1H, d, J=2.1Hz), 9.61 (1H, s), 13.34 (1H, s).

A-145-[(N′,N′-dimethylhydrazinooxalyl)amino]-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide

NMR (CDCl₃) d: 2.73 (6H, s), 3.43 (3H, s), 3.58-3.67 (2H, m), 3.66-3.73(2H, m), 4.21 (2H, s), 6.98-7.07 (2H, m), 7.14-7.20 (2H, m), 7.87 (1H,d, J=2.1 Hz), 8.46-8.16 (m, 2H), 9.03 (1H, d, J=2.1 Hz), 9.60 (1H, s),13.36 (1H, s).

A-15N-[3-(4-fluorobenzyl)-8-hydroxy-7-(2-methoxyethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′,N′-dimethyloxalamide

NMR (CDCl₃) d: 3.13 (3H, s), 3.42 (6H, s), 3.58-3.63 (2H, m), 3.65-3.71(2H, m), 4.20 (2H, s), 6.98-7.06 (2H, m), 7.14-7.22 (2H, m), 7.89 (1H,s), 8.09 (1H, br s), 9.03 (1H, d, J=2.1 Hz), 9.61 (1H, br s), 13.31 (1H,s).

Example A-16 to A-19

According to the method of Example A-4, Compounds A-16 to A-19 weresynthesized.

A-16 3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-dicarboxylicacid bis[(2-methoxyethyl)amide]

NMR (CDCl₃) d: 3-0.44 (3H, s), 3.45 (3H, s), 3.61-3.69 (4H, m),3.69-3.78 (4H, m), 4.20 (2H, s), 6.97-7.05 (2H, m), 7.16-7.23 (2H, m),7.99 (1H, br s), 8.15 (1H, br s), 9.01 (1H, d, J=2.0 Hz), 9.74 (1H, d,J=2.0 Hz), 13.79 (1H, s).

A-175-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide

NMR (CDCl₃) d: 2.83 (6H, s), 3.48 (3H, s), 3.66-3.71 (2H, m), 3.71-3.78(2H, m), 4.21 (2H, s), 6.96-7.05 (2H, m), 7.17-7.24 (2H, m), 8.18 (1H,br s), 8.34 (1H, br s), 9.01 (1H, d, J=2.1 Hz), 9.56 (1H, d, J=2.1 Hz),13.77 (1H, br s).

A-18 3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-carboxylic acid7-[(2-methoxyethyl)amide] 5-[(2-morpholine-4-ylethyl)amide]

NMR (CDCl₃) d: 2.55-2.59 (4H, m), 2.68 (2H, t, J=6.0 Hz), 3.41 (3H, s),3.58-3.64 (4H, m), 3.72-3.81 (6H, m), 4.20 (2H, s), 6.96-7.04 (2H, m),7.15-7.22 (2H, m), 8.16-8.25 (2H, m), 9.00 (1H, d, J=2.2 Hz), 9.74 (1H,d, J=2.2 Hz), 13.77 (1H, br s).

A-19 3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-carboxylic acid7-[(2-methoxyethyl)amide] 5-[(2-morpholine-4-ylpropyl)amide]

NMR (CDCl₃) d: 1.95 (2H, t, J=6.2 Hz), 2.58-2.70 (6H, m), 3.42 (3H, s),3.57-3.69 (4H, m), 3.69-3.80 (6H, m), 4.20 (2H, s), 6.96-7.05 (2H, m),7.16-7.23 (2H, m), 8.54 (2H, br s), 9.00 (1H, d, J=2.0 Hz), 9.72 (1H, d,J=2.0 Hz), 13.89 (1H, br s).

Example A-20

The present invention also comprehends the following compounds. Suchcompounds may be synthesized in the same manner as the above Examples.

Structure of —NR²R³ moiety is shown below.

TABLE 2 No. Structure 001

002

003

004

005

006

007

008

009

010

011

012

013

014

015

016

017

018

019

020

TABLE 3 No. Structure 021

022

023

024

025

026

027

028

029

030

031

032

033

034

035

036

037

038

039

040

TABLE 4 No. Structure 041

042

043

044

045

046

047

048

049

050

051

052

053

054

055

056

057

058

059

060

TABLE 5 No. Structure 061

062

063

064

065

066

067

068

069

070

071

072

073

074

075

076

077

078

079

080

TABLE 6 No. Structure 081

082

083

084

085

086

087

088

089

090

091

092

093

094

095

096

097

098

099

100

TABLE 7 No. Structure 101

102

103

104

105

106

107

108

109

110

111

112

113

114

Example B-1

B-13-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)-[1,6]naphthyridine-7-carboxylicacid (2-hydroxybutyl)amide

1) A dichloromethane (100 ml) solution of Compound 15 (8.5 g, 20.4 mmol)and pyridine (2.47 ml, 30.6 mmol) was cooled on ice, added withmethoxyacetyl chloride (2.23 ml, 24.5 mmol), stirred or 50 minutes atthe same temperature, and then stirred for 1 hour at room temperature.After adding 0.5 M citric acid aqueous solution, the mixture wasextracted with chloroform. The organic phase was washed with water andsaturated brine. After drying over anhydrous sodium sulfate, the solventwas distilled off, and the resultant residue was subjected to silica gelchromatography. The obtained crystals were washed with methanol, to givemethyl8-benzyloxy-3-(4-fluorobenzyl)-5-(2-methoxyacetylamino)-[1,6]naphthyridine-7-carbonateb-1 (8.11 g) in 81% yield.

NMR (CDCl₃) d: 3.55 (3H, s), 3.94 (3H, s), 4.13 (2H, s), 4.21 (2H, s),5.52 (2H, s), 7.00-7.06 (2H, m), 7.19-7.27 (2H, m), 7.33-7.43 (3H, m),7.57-7.61 (2H, m), 8.06 (1H, s), 8.98 (1H, br s), 9.01 (1H, d, J=1.8Hz).

2) According to the method of 5) in Example A-3, from the above Compoundb-1 (7.86 g, 16.1 mmol),8-benzyloxy-3-(4-fluorobenzyl)-5-(2-methoxyacetylamino)-[1,6]naphthyridine-7-carboxylicacid b-2 (6.85 g) was obtained in 90% yield.

NMR (CDCl₃) d: 3.57 (3H, s), 4.15 (2H, s), 4.23 (2H, s), 5.72 (2H, s),7.00-7.08 (2H, m), 7.18-7.23 (2H, m), 7.34-7.39 (3H, m), 7.56-7.60 (2H,m), 8.09 (1H, s), 9.06 (1H, d, J=2.1 Hz), 9.06 (1H, br s).

3) According to the method of 9) in Example A-1, from the above Compoundb-2 (200 mg, 0.421 mmol),8-benzyloxy-3-(4-fluorobenzyl)-5-(2-methoxyacetylamino)-[1,6]naphthyridine-7-carboxylicacid (2-hydroxybutyl)amide b-3 (223 mg) was obtained in 97% yield.

NMR (DMSO-d₆) d: 0.94 (3H, t, J=7.4 Hz), 1.48 (2H, qui, J=7.4 Hz),3.21-3.31 (1H, m), 3.51-3.67 (2H, m), 3.55 (3H, s), 4.16 (2H, s), 4.21(2H, s), 5.56 (2H, s), 6.99-7.08 (2H, m), 7.18-7.24 (2H, m), 7.35-7.43(3H, m), 7.56-7.60 (2H, m), 8.11 (1H, br s), 8.20-8.24 (1H, m), 9.00(1H, d, J=1.8 Hz), 9.03 (1H, br s).

4) According to the method of 11) in Example A-1, B-1 (126 mg) wasobtained in 68% yield from the above Compound b-3 (215 mg, 0.408 mmol).

Melting point: 75-77° C.

NMR (CDCl₃) d: 1.03 (3H, t, J=7.4 Hz), 1.51-1.67 (2H, m), 3.37 (1h, ddd,J=14.0, 7.9, 5.9 hz), 3.57 (3H, s), 3.72 (1H, ddd, J=14.0, 6.9, 3.0 Hz),3.78-3.85 (1H, m), 4.12 (2H, s), 4.20 (2H, s), 6.98-7.07 (2H, m),7.14-7.20 (2H, m), 7.92 (1H, s), 8.20 (1H, t, J=6.1 Hz), 8.69 (1H, s),8.98 (1H, d, J=2.1 Hz), 13.18 (1H, br s).

Example B-2

B-2 3-(4-fluorobenzyl)-8-hydroxy-5-methyl[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide

1) Compound 8 (2.113 g, 4.0 mmol) and potassium phosphate (4.24 g, 20mmol) were put into a reaction flask, and after drying in vacuo,tetrakistriphenyl phosphine palladium (462 mg, 0.4 mmol), methylboronate (599 mg, 10 mmol) was added and suspended in dioxane (48 ml).Vacuum deaeration under stirring at room temperature was carried outfollowed by heating under stirring in an oil bath at 100° C. After 3.5hours, the reaction was left overnight at room temperature. On the nextday, the reaction mixture was added with ethyl acetate ester (150 ml)and water (150 ml), as well as 10% citric acid (60 ml), shaken forseparation, washed once with brine, dried over sodium sulfate, and thesubjected to distillation under reduce pressure. The obtained residue(2.58 g) was subjected to high flash column chromatography (hexane:ethylacetate ester (2:1)), and the gathered fractions were combined andsubjected to distillation. The residue (467 mg) was added withdiisopropyl ether and caused to crystallize, to give methyl8-benzyloxy-3-(4-fluorobenzyl)-5-methyl[1,6]naphthyridine-7-carbonateb-4 (407 mg) as ocher crystals in 24.4% yield.

NMR (CDCl₃) d: 2.90 (3H, s), 3.95 (3H, s), 4.23 (2H, s), 5.50 (2H; s),7.02-7.08 (2H, m), 7.19-7.23 (2H, m), 7.32-7.41 (3H, m), 7.58-7.61 (2H,m), 8.13 (1H, m), 9.04 (1H, d, J=2.1 Hz).

2) According to the method of 5) in Example A-3, from the above Compoundb-4 (815 mg, 1.96 mmol),8-benzyloxy-3-(4-fluorobenzyl)-5-methyl[1,6]naphthyridine-7-carboxylicacid b-5 (740 mg) was obtained in 93.9% yield.

NMR (CDCl₃) d: 2.87 (3H, s), 4.25 (2H, s), 5.62 (2H, s), 7.03-7.09 (2H,m), 7.18-7.23 (2H, m), 7.31-7.38 (3H, m), 7.64-7.66 (2H, m), 8.13 (1H,m), 9.09 (1H, d, J=2.1 Hz).

3) According to the method of 9) in Example A-1, from the above Compoundb-5 (201 mg, 0.5 mmol),8-benzyloxy-3-(4-fluorobenzyl)-5-methyl[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl) amide b-6 (180 mg) was obtained in 78.3% yield.

NMR (DMSO-d₆) d: 2.88 (3H, s), 3.36 (3H, s), 3.54-3.58 (2H, m),3.64-3.70 (2H, m), 4.22 (2H, s), 5.48 (2H, s), 7.02-7.08 (2H, m),7.18-7.23 (2H, m), 7.31-7.40 (3H, m), 7.65-7.67 (2H, m), 8.11 (1H, m),8.24 (1H, m), 9.03 (1H, d, J=2.1 Hz).

4)-According to the method of 11) in Example A-1, from the aboveCompound b-6 (177 mg, 0.385 mmol), Compound B-2 (109 mg) was obtained in76.8% yield.

Melting point: 167-168° C.

Elemental analysis for C₂₀H₂₀FN₃O₃

Calcd.(%): C, 65.03; H, 5.46; F, 5.14; N, 11.38.

Found.(%): C, 64.91; H, 5.51; F, 5.08; N, 11.26.

NMR (CDCl₃) d: 12.76 (3H, s), 3.44 (3H, s), 3.61-3.64 (2H, m), 3.68-3.73(2H, m), 4.21 (2H, s), 7.01-7.06 (2H, m), 7.16-7.21 (2H, m), 8.03 (1H,d, J=2.1 Hz), 8.40 (1H, m), 9.01 (1H, d, J=2.1 Hz), 13.09 (1H, s).

Example B-3

B-33-(4-fluorobenzyl)-8-hydroxy-5-(1-hydroxyethyl)[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl) amide

1) To Compound 8 (1.585 g, 3 mmol) was added toluene (60 ml), and theresultant solution was stirred at room temperature in nitrogen gas flow,added with tetrakistriphenylphosphine palladium (522 mg, 0.452 mmol)followed by tributyl(1-ethoxyvinyl)tin (2.04 ml, 6.04 mmol), and heatedin an oil bath at 100° C. under stirring. After 4 hours, the mixture waslet stand at room temperature, and on the next day, the reaction mixturewas subjected to distillation under reduced pressure and added withtetrahydrofuran (60 ml). Then the mixture was stirred at roomtemperature, added with 2N hydrochloric acid (6 ml), stirred for 30minutes, added with ethyl acetate ester (140 ml) and water (100 ml),shaken for separation, and washed with saturated brine. Then the mixturewas concentrated under reduced pressure, added with an water (20 mL)solution of potassium fluoride (4 g), and stirred for 30 minutes at roomtemperature. Then the precipitated insoluble matters were filtered off,and washed with ethyl acetate ester, and the filtration wash liquid wasgathered and subjected to separation. After one washing with water anddrying over sodium sulfate, distillation under reduce pressure wasconducted. The obtained residue (2.65 g) was subjected to high flashcolumn chromatography (hexane:ethyl acetate ester (7:1)), and thegathered fractions were combined and subjected to distillation. Theobtained residue was crystallized from diisopropyl ether, to give methyl5-acetyl-8-benzyloxy-3-(4-fluorobenzyl)[1,6]naphthyridine-7-carbonateb-7 (1.164 g) as yellow powder in 87.3% yield.

NMR (CDCl₃) d: 2.85 (3H, s), 3.96 (3H, s), 4.21 (2H, s), 5.70 (2H, s),7.00-7.06 (2H, m), 7.19-7.24 (2H, m), 7.33-7.40 (3H, m), 7.53-7.56 (2H,m), 9.01 (1H, d, J=2.1 Hz), 9.33 (1H, m).

2) To the above Compound b-7 (441 mg, 0.992 mmol) was added methanol (40ml), and the mixture was warmed on water bath and stirred at roomtemperature. After adding sodium borohydride (38 mg, 1.004 mmol) at atime, the mixture was stirred. After 2 hours, the reaction solution waspoured into the ammonium chloride aqueous solution and ice water,extracted with ethyl acetate ester, washed with brine, dried over sodiumsulfate, and then subjected to distillation under reduced pressure. Theresultant residue (0.56 g) was subjected to high flash chromatography(toluene:acetone (9:1)), and gathered fractions were combined andsubjected to distillation. The obtained residue was dissolved in ethylacetate ester, and added with 2N hydrochloric acid and water. Themixture was shaken for separation, washed with water, washed with sodiumhydrogen carbonate aqueous solution, and further washed once with water.Then the mixture was dried over sodium sulfate and subjected todistillation under reduced pressure, to give methyl8-benzyloxy-3-(4-fluorobenzyl)-5-(1-hydroxyethyl)[1,6]naphthyridine-7-carbonateb-8 (406 mg) as oil in 91.6% yield.

NMR (CDCl₃) d: 1.55 (3H, d, J=6.6 Hz), 3.94 (3H, s), 4.23 (3H, s), 4.68(1H, bs), 5.44 (1H, m), 5.52 (2H, s), 7.03-7.08 (2H, m), n 7.17-7.22(2H, m), 7.34-7.44 (3H, m), 7.58-7.60 (2H, m), 8.15 (1H, d, J=2.1 Hz),9.06 (1H, d, J=2.1 Hz).

3) According to the method of 5) in Example A-3, from the above Compoundb-8 (480 mg, 1.08 mmol),8-benzyloxy-3-(4-fluorobenzyl)-5-(1-hydroxyethyl)[1,6]naphthyridine-7-carboxylicacid b-9 (420 mg) was obtained in 90.3% yield.

NMR (CDCl₃) d: 1.63 (3H, d, J=6.6 Hz), 4.25 (2H, s), 5.49 (1H, quart,J=6.6 Hz), 5.69 (2H, s), 7.03-7.09 (2H, m) 7.18-7.23 (2H, m), 7.35-7.38(3H, m), 7.59-7.62 (2H, m), 8.36 (1H, m), 9.08 (1H, d, J=2.1 Hz).

4) According to the method of 9) in Example A-1, NMR (DMSO-d₆) d:8-benzyloxy-3-(4-fluorobenzyl)-5-(1-hydroxyethyl)[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide b-10 (201 mg) was obtained in 88.9% yieldfrom the above Compound b-9 (200 mg, 0.463 mmol).

NMR (DMSO-d₆) d: 1.58 (3H, d, K=6.6 hz), 3.34 (3H, s), 3.52-3.55 (2H,m), 3.63-3.67 (2H, m), 4.23 (2H, s), 4.45 (1H, bs), 5.43-5.56 (1H, m),5.50 (1H, d, J=10.5 Hz), 5.54 (1H, d, J=10.5 Hz), 7.02-7.08 (2H, m),7.18-7.22 (2H, m) 7.33-7.41 (3H, m), 7.63-7.65 (2H, m), 7.96 (1H, m),8.18 (1H, d, J=2.1 Hz), 9.05 (1H, d, J=2.1 Hz).

5) According to the method of 11) in Example A-1, Compound B-3 (136 mg)was obtained in 84% yield from the above Compound b-10 (198 mg, 0.404mmol).

Melting point: 179° C.

Elemental analysis for C₂₁H₂₂FN₃O₄

Calcd.(%): C, 63.15; H, 5.55; F, 4.76; N, 10.52.

Found.(%): C, 63.15; H, 5.61; F, 4.66; N, 10.38.

NMR (CDCl₃) d: 1.56 (3H, d, J=6.6 Hz) 3.43 (3H, s), 3.61-3.64 (2H, m),3.70-3.75 (2H, m), 4.22 (2H, s), 5.40 (1H, quart, J=6.6 Hz), 7.01-7.07(2H, m), 7.16-7.20 (2H, m), 8.15 (1H, m), 8.14-8.17 (1H, m), 9.04 (1H,d, J=2.1 Hz).

Example B-4

B-43-(4-fluorobenzyl)-8-hydroxy-5-(3-methoxypropenyl)[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide

1) To Compound 10 (286 mg, 0.5 mmol) and tetrakistriphenyl phosphinepalladium (30 mg, 0.026 mmol) was added a dimethylformamide (4 ml)solution of2-((E)-3-methoxy-propenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (142mg, 0.65 mmol), followed by an aqueous solution of 2 moles of potassiumcarbonate (0.66 ml, 1.32 mmol), and after vacuum deaeration understirring at room temperature, and replacement with nitrogen, thereaction was heated under stirring in an oil bath at 100° C. After 3hours, to the reaction mixture were added and dissolved ethyl acetateand water, and was added 10% citric acid (8 ml), and then the mixturewas shaken for separation, washed twice with water, dried over sodiumsulfate, and subjected to distillation under reduced pressure. Theresidue was subjected to high flash column chromatography(toluene:acetone (4:1)), and the obtained residue (170 mg) wascrystallized from diisopropyl ether, to give8-benzyloxy-3-(4-fluorobenzyl)-5-(3-methoxypropenyl)[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)amide b-11 (135 mg) in 52.3% yield.

NMR (CDCl₃) d: 3.38 (3H, s), 3.50 (3H, s), 3.56-3.59 (2H, m), 3.66-3.71(2H, m), 4.21 (2H, s), 4.27 (2H, dd, J=1.8, 4.5 Hz), 5.50 (2H, s),7.01-7.39 (9H, m), 7.67-7.70 (2H, m), 8.21 (1H, m), 8.31 (1H, d, J=1.8Hz), 9.01 (1H, d, J=1.8 Hz).

2) According to the method 11) of Example A-1, Compound B-4 (140 mg) wasobtained in 84.8% yield from the above Compound b-11 (200 mg, 0.388mmol).

Melting point: 125-126° C.

Elemental analysis for C₂₃H₂₄FN₃O₄

Calcd.(%): C, 64.93; H, 5.69; F, 4.47; N, 9.88.

Found.(%): C, 64.78; H, 5.54; F, 4.24; N, 9.75.

NMR (CDCl₃) d: 3.44 (3H, s), 3.49 (3H, s), 3.62-3.65 (2H, m), 3.69-3.74(2H, m), 4.21 (2H, s), 4.24 (2H, dd, J=1.8, 5.1 Hz), 6.89-6.97 (1H, m),7.00-7.07 (2H, m), 7.15-7.26 (3H, m), 8.25 (1H, d, J=1.8 Hz), 8.39 (1H,m), 9.00 (1H, d, J=2.1 Hz), 13.27 (1H, s).

Example B-5 to B-16

According to the method of Example B-1, Compounds B-5 to B-16 weresynthesized.

Example B-53-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (3-methoxypropyl) amide

Melting point: 159-160° C.

Elemental analysis for C₂₃H₂₅FN₄O₅

Calcd.(%): C, 60.52; H, 5.52; F, 4.16; N, 12.27.

Found.(%): C, 60.47; H, 5.60; F, 4.09; N, 12.23.

NMR (CDCl₃) d: 1.90-1.98 (2H, m), 3.41 (3H, s), 3.55-3.64 (5H, m), 3.57(3H, s), 4.13 (2H, s), 4.20 (2H, s), 6.99-7.05 (2H, m), 7.15-7.20 (2H,m), 7.94 (1H, s), 8.23-8.27 (1H, m), 9.00 (1H, d, J=2.0 Hz), 13.37 (1H,brs).

Example B-63-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-diisopropylaminoethyl)amide

Melting point: 69-70° C.

Elemental analysis for C₂₇H₃₄FN₅O₄

Calcd.(%): C, 63.39; H, 6.70; F, 3.71; N, 13.69.

Found.(%): C, 60.69; H, 6.65; F, 3.34; N, 13.10.

NMR (CDCl₃) d: 1.07 (12H, d, J=5.8 Hz), 2.73 (2H, brs), 3.08 (2H, brs),3.44 (2H, brs), 3.58 (3H, s), 4.12 (2H, s), 4.20 (2H, s), 6.99-7.05 (2H,m), 7.15-7.19 (2H, m), 7.97 (1H, s), 8.34 (1H, brs), 8.62 (1H, brs),8.99 (1H, d, J=2.1 Hz), 13.39 (1H, brs).

Example B-73-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-isopropoxyethyl)amide

Melting point: 149-150° C.

Elemental analysis for C₂₄H₂₇FN₄O₅

Calcd.(%): C, 61.27; H, 5.78; F, 4.04; N, 11.91.

Found.(%): C, 61.16; H, 5.88; F, 3.92; N, 11.79.

NMR (CDCl₃) d: 1.21 (6H, d, J=6.1 Hz), 3.58 (3H, s), 3.62-3.70 (5H, m),4.13 (2H, s), 4.20 (2H, s), 6.99-7.05 (2H, m), 7.15-7.20 (2H, m), 7.95(1H, s), 8.16 (1H, brs), 8.64 (1H, s), 8.99 (1H, d, J=1.9 Hz), 13.26(1H, brs).

Example B-83-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-cyanoethyl)amide

Melting point: 173-175° C.

NMR (CDCl₃) d: 2.79 (2H, t, J=6.4 Hz), 3.59 (3H, s), 3.78 (2H, q, J=6.4Hz), 4.14 (2H, s), 4.21 (2H, s), 6.99-7.06 (2H, m), 7.94 (1H, d, J=2.1Hz), 8.21 (1H, t, J=6.1 Hz), 8.69 (1H, s), 9.02 (1H, d, J=2.1 Hz), 12.79(1H, br s).

Example B-93-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-dimethylaminoethyl)amide

Melting point: 164-166° C.

NMR (DMSO-d₆) d: 2.21 (6H, s), 2.45-2.51 (2H, m), 3.39 (3H, s),3.43-3.50 (2H, m), 4.15 (2H, s), 4.25 (2H, s), 7.12-7.19 (2H, m),7.32-7.38 (2H, m), 8.12 (1H, s), 8.76 (1H, t, J=5.6 Hz), 9.08 (1H, d,J=1.8 Hz), 10.26 (1H, s), 13.49 (1H, br s).

Example B-103-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-hydroxy-1-methylethyl)amide

Melting point: 85-87° C.

NMR (CDCl₃) d: 1.36 (3H, d, J=6.9 Hz), 3.58 (3H, s), 3.71 (1H, dd,J=11.1, 5.8 Hz), 3.84 (1H, dd, J=11.1, 3.8 Hz), 4.13 (2H, s), 4.20 (2H,s), 4.25-4.35 (1H, m), 6.99-7.06 (2H, m), 7.15-7.21 (2H, m), 7.91 (1H,s), 7.93 (1H, s), 8.67 (1H, s), 8.99 (1H, d, J=2.1 Hz), 13.18 (1H, brs).

Example B-11 Methyl2-{[3-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carbonyl]amino}propionate

Melting point: 181-182° C.

Elemental analysis for C₂₃H₂₃FN₄O₆

Calcd.(%): C, 58.72; H, 4.93; F, 4.04; N, 11.91.

Found.(%): C, 58.62; H, 4.84; F, 3.80; N, 11.86.

NMR (CDCl₃) d: 1.58 (3H, s), 3.59 (3H, s), 3.82 (3H, s), 4.14 (2H, s),4.20 (2H, s), 4.77-4.87 (1H, m), 7.00-7.05 (2H, m), 7.15-7.20 (2H, m),7.94 (1H, m), 8.26 (1H, d, J=7.8 Hz), 8.66 (1H, s), 9.00 (1H, d, J=2.1Hz), 12.95 (1H, s).

Example B-123-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (3-diethylaminopropyl)amide

NMR (CDCl₃) d: 1.13 (3H, d, J=6 Hz), 1.25 (6H, trip, J=6.9 Hz), 2.06(2H, bs), 2.94 (6H, bs), 3.58 (3H, s), 3.58-3.67 (2H, m), 4.13 (2H, s),4.20 (2H, s), 6.99-7.05 (2H, m), 7.15-7.20 (2H, m), 7.96 (1H, s), 8.65(1H, bs), 8.74 (1H, bs), 8.99 (1H, d, J=2.1 Hz), 13.15 (1H, bs).

Example B-133-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (3-dimethylaminopropyl)amide

NMR (CDCl₃) d: 1.96-2.00 (2H, m), 2.51 (6H, s), 2.71-2.75 (2H, m),3.56-3.60 (2H, m), 3.58 (3H, s), 4.13 (2H, s), 4.20 (2H, s), 6.99-7.05(2H, m), 7.15-7.20 (2H, m), 7.96 (1H, m), 8.67 (1H, bs), 8.70 (1H, s),8.99 (1H, d, J=2.1 Hz), 13.30 (1H, bs).

Example B-143-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-ethoxyethyl)amide

Melting point: 175-177° C.

Elemental analysis for C₂₃H₂₅FN₄O₅

Calcd.(%): C, 60.52; H, 5.52; F, 4.16; N, 12.27.

Found.(%): C, 60.59; H, 5.38; F, 3.93; N, 12.17.

NMR (CDCl₃) d: 1.25 (3H, t, J=7.0 Hz), 3.56-3.62 (5H, m), 3.64-3.73 (4H,m), 4.14 (2H, s), 4.20 (2H, s), 6.99-7.04 (2H, m), 7.15-7.22 (2H, m),7.95 (1H, s), 8.12 (1H, m), 8.64 (1H, s), 9.00 (1H, s), 13.26 (1H, s).

Example B-15 Methyl3-([3-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carbonyl]amino)propionate

Melting point: 168-170° C.

Elemental analysis for C₂₃H₂₃FN₄O₆

Calcd.(%): C, 58.72; H, 4.93; F, 4.04; N, 11.91.

Found.(%): C, 58.56; H, 4.83; F, 3.90; N, 11.80.

NMR (CDCl₃) d: 2.72 (2H, t, J=6.2 Hz), 3.74-3.81 (5H, m), 4.13 (2H, s),4.21 (2H, s), 6.99-7.05 (2H, m), 7.15-7.20 (2H, m), 7.93 (1H, s), 8.22(1H, m), 8.63 (1H, s), 9.00 (1H, s), 13.18 (1H, s).

Example B-163-(4-fluorobenzyl)-8-hydroxy-5-(2-methoxyacetylamino)[1,6]naphthyridine-7-carboxylicacid (2-methoxyethyl)methylamide

Melting point: 66-68° C.

Elemental analysis for C₂₃H₂₃FN₄O₆

Calcd.(%): C, 58.72; H, 4.93; F, 4.04; N, 11.92.

Found.(%): C, 58.56; H, 4.83; F, 3.90; N, 11.80.

NMR (CDCl₃) d: 3.36 (6H, s), 3.55 (3H, s), 3.72 (2H, t, J=5.2 Hz), 4.11(2H, s), 4.20 (2H, s), 6.99-7.05 (2H, m), 7.15-7.20 (2H, m), 7.92 (1H,s), 8.66 (1H, bs), 8.98 (1H, s).

Example B-17

According to the method of Example B-2, Compound B-17 was synthesized.

Example B-173-(4-fluorobenzyl)-8-hydroxy-5-methyl[1,6]naphthyridine-7-carboxylicacid N′,N′-dimethylhydrazide

Melting point: 137-139° C.

Elemental analysis for C₁₉H₁₉FN₄O₂

Calcd.(%): C, 64.40; H, 5.40; F, 5.36; N, 15.81.

Found.(%): C, 64.14; H, 5.30; F, 5.24; N, 15.51.

NMR (CDCl₃) d: 2.76 (3H, s), 2.80 (6H, s), 4.22 (2H, s), 7.01-7.06 (2H,m), 7.16-7.21 (2H, m), 8.03 (1H, m), 8.80 (1H, bs), 9.02 (1H, d, J=2.1Hz), 12.91 (1H, bs).

Example B-18

According to the method of Example B-3, Compound B-18 was synthesized.

Example B-183-(4-fluorobenzyl)-8-hydroxy-5-(1-hydroxyethyl)[1,6]naphthyridine-7-carboxylicacid N′,N′-dimethylhydrazide

Melting point: 114-116° C.

Elemental analysis for C₂₀H₂₁FN₄O₃.0.9H₂O

Calcd.(%): C, 59.96; H, 5.74; F, 4.74; N, 13.99.

Found.(%): C, 60.05; H, 5.68; F, 4.94; N, 13.70.

NMR (CDCl₃) d: 1.57 (3H, d, J=6.3 Hz), 2.82 (6H, s), 3.59 (1H, bs), 4.22(2H, s), 5.39 (1H, d, J=5.4 Hz), 7.01-7.07 (2H, m), 7.16-7.20 (2H, m),8.04 (1H, s), 8.57 (1H, bs), 9.04 (1H, s), 13.16 (1H, bs).

Example B-19 to B-20

According to the method of Example B-4, Compounds B-19 to 20 weresynthesized.

Example B-193-(4-fluorobenzyl)-8-hydroxy-5-(3-methoxypropenyl)[1,6]naphthyridine-7-carboxylicacid N′,N′-dimethylhydrazide

Melting point: 115-116° C.

Elemental analysis for C₂₂H₂₃FN₄O₃

Calcd.(%): C, 64.38; H, 5.65; F, 4.63; N, 13.65.

Found.(%): C, 64.23; H, 5.65; F, 4.35; N, 13.34.

NMR (CDCl₃) d: 2.82 (6H, s), 3.49 (3H, s), 4.21 (2H, s), 4.24 (1H, d,J=1.8 Hz), 4.26 (1H, d, J=1.8 Hz), 6.86-6.94 (1H, m), 7.00-7.06 (2H, m),7.15-7.25 (3H, m), 8.24 (1H, d, J=1.84 Hz), 8.77 (1H, bs), 9.01 (1H, d,J=1.8 Hz), 13.07 (1H, bs).

Example B-203-(4-fluorobenzyl)-8-hydroxy-5-(3-methoxypropenyl)[1,6]naphthyridine-7-carboxylicacid (2-dimethylaminoethyl)amide hydrochloride monohydrate

Melting point: 156-158° C.

Elemental analysis for C₂₄H₂₇FN₄O₃.HCl.H₂O

Calcd.(%): C, 58.47; H, 6.13; Cl, 7.19; F, 3.85; N, 11.37.

Found.(%): C, 58.39; H, 16.16; Cl, 7.22; F, 3.99; N, 11.36.

NMR (d6-DMSO)) d: 2.85 (6H, s), 3.38 (3H, s), 3.74-3.76 (2H, m),4.23-4.27 (4H, m), 7.13-7.18 (2H, m), 7.30-7.52 (4H, m), 8.79 (1H, s),9.07 (1H, m), 9.32-9.36 (1H, m), 9.80 (1H, bs), 13.35 (1H, bs).

Example B-21 to B-24

According to the method of Example A-4, Compounds B-21 to B-24 weresynthesized.

Example B-213-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-dicarboxylic acid5-tert-butylamide 7-[(2-hydroxybutyl)amide]

NMR (CDCl₃) d: 1.05 (3H, t, J=7.5 Hz), 1.53 (9H, s), 1.58-1.74 (2H, m),3.30-3.40 (1H, m), 3.79-3.90 (2H, m), 4.20 (2H, s), 6.96-7.04 (2H, m),7.16-7.21 (2H, m), 7.52 (1H, s), 8.13-8.17 (1H, m), 8.98 (1H, d, J=2.2Hz), 9.78 (1H, d, J=2.2 Hz), 13.59 (1H, br s).

Example B-223-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-dicarboxylic acid7-[(2-hydroxybutyl)amide] 5-[(2-methoxyethyl)amide]

NMR (CDCl₃) d: 1.05 (3H, d, J=7.5 Hz), 1.54-1.70 (2H, m), 3.33-3.42 (1H,m), 3.42 (3H, s), 3.60-3.64 (2H, m), 3.66-3.72 (2H, m), 3.76-3.91 (2H,m), 4.19 (2H, s), 6.97-7.04 (2H, m), 7.16-7.21 (2H, m), 8.05-8.11 (1H,m), 8.29-8.36 (1H, m), 8.98 (1H, d, J=2.1 Hz), 9.70 (1H, d, J=2.1 Hz),13.69 (1H, br s).

Example B-233-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-dicarboxylic acid7-[(2-hydroxybutyl)amide]5-{[3-(2-oxopyrrolidine-1-yl)propyl]amide}

NMR (CDCl₃) d: 1.03 (3H, d, J=7.4 Hz), 1.54-1.64 (2H, m), 1.78-1.86 (2H,m), 2.08-2.19 (2H, m), 2.53-2.56 (2H, m), 3.33-3.56 (7H, m), 3.73-3.85(2H, m), 4.20 (2H, s), 6.95-7.04 (2H, m), 7.17-7.22 (2H, m), 9.00 (1H,d, J=2.1 Hz), 9.04-9.11 (1H, m), 9.19 (1H, t, J=6.3 Hz), 9.94 (1H, d,J=2.1 Hz), 14.03 (1H, s).

Example B-243-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5,7-dicarboxylic acid7-[(2-hydroxybutyl)amide] 5-[(tetrahydrofuran-2-ylmethyl)amide]

NMR (CDCl₃) d: 1.05 (3H, t, J=7.5 Hz), 1.56-1.72 (2H, m), 1.90-2.01 (3H,m), 2.01-2.18 (1H, m), 3.31-3.43 (2H, m), 3.76-3.98 (5H, m), 4.09-4.20(1H, m), 4.20 (2H, s), 6.97-7.04 (2H, m), 7.16-7.22 (2H, m), 8.11-8.18(1H, m), 8.41 (1H, br s), 8.99 (1H, d, J=2.0 Hz), 9.73 (1H, s), 13.67(1H, br s).

Example B-25 to B-29

According to the method of Example A-3, Compounds B-25 to B-29 weresynthesized.

Example B-25N-[7-(N′,N′-dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-yl]-N′-(2-methoxyethyl)oxalamide

Melting point: 167-169° C.

NMR (CDCl₃) d: 2.79 (6H, s), 3.43 (3H, s), 3.55-3.67 (4H, m), 4.21 (2H,s), 6.99-7.06 (2H, m), 7.15-7.20 (2H, m), 7.74-7.80 (1H, m), 7.94 (1H,d, J=1.4 Hz), 8.52 (1H, br s), 9.03 (1H, d, J=2.1 Hz), 9.63 (1H, s),13.08 (1H, brs).

Example B-26N-[7-(N′,dimethylhydrazinocarbonyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-yl]-N′,N′-dimethyloxalamide

Melting point: 125-128° C.

NMR (CDCl₃) d: 2.78 (6H, s), 3.13 (3H, s), 3.43 (3H, s) 4.21 (2H, s),6.98-7.06 (2H, m), 7.15-7.21 (2H, m), 7.88 (1H, s), 8.56 (1H, br s),9.04 (1H, d, J=2.0 Hz), 9.66 (1H, br s), 13.07 (1H, br s).

Example B-27N-[3-(4-fluorobenzyl)-8-hydroxy-7-(2-hydroxyethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′-methyloxalamide

Melting point: 136-137° C.

NMR (CDCl₃) d: 3.02 (3H, d, J=5.2 Hz), 3.65-3.71 (2H, m), 3.87-3.93 (2H,m), 4.19 (2H, s), 6.98-7.05 (2H, m), 7.13-7.19 (2H, m), 7.53 (1H, d,J=5.2 Hz), 7.92 (1H, s), 8.17-8.23 (1H, m), 9.01 (1H, d, J=2.0 Hz),13.19 (1H, s).

Example B-28N-[3-(4-fluorobenzyl)-8-hydroxy-7-(2-hydroxy-1-methylethylcarbamoyl)[1,6]naphthyridine-5-yl]-N′-methyloxalamide

Melting point: 131-133° C.

NMR (CDCl₃) d: 1.36 (3H, d, J=6.7 Hz), 3.03 (3H, d, J=5.2 Hz), 3.71 (1H,dd, J=11.1, 5.9 Hz), 3.84 (1H, dd, J=11.1, 3.8 Hz), 4.19 (2H, s),4.26-4.35 (1H, m), 6.98-7.06 (2H, m), 7.14-7.19 (2H, m), 7.49 (1H, d,J=5.2 Hz), 7.92 (1H, d, J=2.0 Hz), 9.02 (1H, d, J=2.0 Hz), 9.65 (1H, s),13.21 (1H, s).

Example B-29N-[7-(3-dimethylaminopropylcarbamoyl)-3-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-5-yl]-N′-methyloxalamide

NMR (CDCl₃) d: 1.83 (2H, m), 2.33 (6H, s), 2.49-2.55 (2H, m), 3.03 (3H,d, J=5.2 Hz), 3.54-3.63 (2H, m), 4.19 (2H, s), 6.98-7.05 (2H, m),7.13-7.19 (2H, m), 7.49 (1H, br s), 7.94 (1H, s), 8.86 (1H, br s), 9.02(1H, s), 9.62 (1H, br s), 13.52 (1H, br s).

Example B-30

The following compounds were synthesized.

Experimental Example 1

The inhibitory activities against integrase were determined by the assaydescribed below.

-   (1) Preparation of DNA Solutions

A substrate DNA solution (2 pmol/μl) and a target DNA solution (5pmol/μl) were prepared in the manner as described in Experimentalexample 1 of WO 2004/024693. Before using the DNA solutions,complementary chains were annealed by slowly cooling after boiling.Substrate DNA and target DNA had sequences as described in thatExperimental example.

-   (2) Determination of Inhibition Rate (IC₅₀ Values)

Streptavidin, obtained from Vector Laboratories, was dissolved in 0.1 Mcarbonate buffer (composition: 90 mM Na₂CO₃, 10 mM NaHCO₃) atconcentration of 40 μg/ml. After coating each well of immunoplates(obtained from NUNC) with 50 μl of the above solution at 4° C. overnight, each well was washed twice with PBS (composition: 13.7 mM NaCl,0.27 mM KCl, 0.43 mM Na₂HPO₄, 0.14 mM KH₂PO₄) and blocked with 300 μl of1% skim milk in PBS for 30 min. Additionally, each well was washed twicewith PBS and added 50 μl of substrate DNA solution (2 pmol/μl). Theimmunoplates were kept at room temperature for 30 min while shaking.Then, each well was washed twice with PBS and once with the distilledwater.

Subsequently, in the each well prepared above were added 51 μl of thereaction solution prepared from 12 μl of the buffer (composition: 150 mMMOPS (pH7.2), 75 mM MnCl₂, 50 mM 2-mercaptoethanol, 25% glycerol, 500μg/ml bovine serum albumin-fraction V), and 39 μl of the distilledwater. Then 9 μl of an integrase solution (30 pmol) was added and mixedwell. In the well of negative control (NC) was added 9 μl of theintegrase dilution buffer (composition: 20 mM MOPS (pH7.2), 400 mMpotassium glutamate, 1 mM EDTA, 0.1% NP-40, 20% glycerol, 1 mM DTT, 4Murea), and mixed well using a plate mixer.

The plates were incubated at 30° C. for 60 minutes. The reactionsolution was removed and washed three times with 250 μl of washingbuffer (composition: 150 mM MOPS (pH7.2), 50 mM 2-mercaptoethanol, 25%glycerol, 500 μg/ml bovine serum albumin-fraction V).

Then each well was added with 53 μl of reaction solution prepared from12 μl of buffer (composition: 150 mM MOPS (pH7.2), 75 mM MgCl₂, 50 mM2-mercaptoethanol, 25% glycerol, 500 μg/ml bovine serum albumin-fractionV) and 41 μl of distilled water. Further, each well was added with 6 μlof DMSO solution of a compound to be tested, and the well of positivecontrol (PC) was added with 6 μl of DMSO, and mixed well by a platemixer. After incubating the plate for 30 minutes at 30° C., was added 1μl of target DNA (5 pmol/μl), and mixed well by a plate mixer.

After incubation for 10 minutes at 30° C., each plate was washed twicewith PBS after removal of the reaction solution. Then, 100 μl of ×2000diluted solution of anti-digoxigenin antibody labeled with alkalinephosphatase (sheep Fab fragment: Boehringer) was added allowed to bindfor 1 hour at 30° C., and washed twice with PBS containing 0.05% Tween20and once with PBS in this sequence. Next, 150 μl of the Alkalinephosphatase coloring buffer (composition: 10 mM p-Nitrophenylphosphate(obtained from Vector Laboratories), 5 mM MgCl₂, 100 mM NaCl, 100 mMTris-HCl (pH 9.5)) was added and allowed to react for 2 hours at 30° C.Then the reaction was terminated by the addition of 50 μl of 1N NaOHsolution. The optical density at 405 nm (OD_(405nm)) of each well wasmeasured and the inhibition rate (IC₅₀) was determined by the followingexpression.The inhibition rate(%)=100[1−{(C abs.−NC abs.)/(PC abs.−NC abs.)}]

C abs.; the OD of the well of the compound

NC abs.: the OD of the negative control (NC)

PC abs.: the OD of the positive control (PC)

Experimental Example 2

The inhibitory activities against HIV cell proliferation were determinedby the assay method described below.

-   (1) HIV (HTLV-IIIB strain) persistence infection human T-cell strain    Molt-4 clone 8 was cultured on RPMI-1640 medium supplemented with    10% fetal bovine serum, and the supernatant was measured for viral    titer after filtration, and stored at −80° C. On the other hand,    each anti-HIV active agent was diluted in the above culture medium    to a predetermined concentration, and each well of a 96-well    microplate was added with 50 μl of the resultant active agent    solution. Then, 100 μl (3.5×10⁴ cells) each of MT-4 cell suspension    was poured into each well, followed by each 50 μl (60 pfu (plaque    forming unit)) of the HIV-containing supernatant diluted with the    above culture medium.-   (2) After incubating for 4 days in a carbon dioxide incubator at 37°    C., every well was added with 30 μl of    3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT)    5 mg/ml), PBS, and incubated for another 1 hour. At this time, since    living cells reduce MTT to cause precipitation of formazane, 150 μl    of cell supernatant was removed from each well, and instead 150 μl    of lysis solution (isopropanol supplemented with 10% Triton X-100    and 0.4% (v/v) HCl) was added, to make formazane eluate by shaking    with a plate mixer. Formazane was observed with OD 560 nm and 690 nm    (reference wavelength) using a micro reader, and the results were    compared with the references. The concentration of Compound at which    50% of cytopathy caused by viruses was inhibited was defined as    EC₅₀.

The results of the above experiment are shown below.

TABLE 8 Experimental Example example 1 (Compound No.) (IC₅₀, μg/ml) A-10.0024 A-2 0.019 A-3 0.019 A-5 0.0045 A-6 0.0056 A-9 0.060 A-10 0.068B-1 0.011 B-2 0.0074 B-3 0.0068 B-4 0.0048 B-5 0.018 B-6 0.072 B-7 0.015B-8 0.012 B-9 0.017 B-10 0.022 B-11 0.024 B-12 0.079 B-13 0.033 B-140.022 B-15 0.021 B-16 0.026 B-17 0.006 B-18 0.017 B-19 0.0046 B-20 0.017B-21 0.0084 B-22 0.017 B-23 0.019 B-24 0.015 B-25 0.019 B-26 0.018 B-270.018 B-28 0.021 B-29 0.025

Formulation Example

The term “active ingredient” means the compounds of the presentinvention, the tautomers, the prodrugs thereof, their pharmaceuticalacceptable salts, or their solvate.

Formulation Example 1

Hard gelatin capsules are prepared using of the following ingredients:

Dose (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation Example 2

A tablet is prepared using of the following ingredients:

Dose (mg/tablet) Active ingredient 250 Cellulose, microcrystals 400Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg.

Formulation Example 3

An aerosol solution is prepared containing the following components:

Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 74.00(chlorodifluoromethane) Total 100.00

The active ingredient is mixed with ethanol and the admixture added to aportion of the propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the reminder of the propellant. The valveunits are then fitted to the container.

Formulation Example 4

Tablets, each containing 60 mg of active ingredient, are made asfollows.

Active ingredient 60 mg Starch 45 mg Microcrystals cellulose 35 mgPolyvinylpyrrolidone (as 10% 4 mg solution in water) Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve, and the mixed thoroughly. The aqueous solutioncontaining polyvinylpyrrolidone is mixed with the resultant powder, andthe admixture then is passed through a No. 14 mesh U.S. sieve. Thegranules so produced are dried at 50° C. and passed through a No. 18mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate,and talc, previously passed through No. 60 mesh U.S. sieve, are thenadded to the granules which, after mixing, are compressed on a tabletmachine to yield tablets each weighing 150 mg.

Formulation Example 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

Active ingredient 80 mg Starch 59 mg Microcrystals cellulose 59 mgMagnesium stearate 2 mg Total 200 mg

The active ingredient, starch, cellulose, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation Example 6

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

Active ingredient 225 mg Saturated fatty acid glycerides 2000 mg Total2225 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7

Suspensions, each containing 50 mg of active ingredient, are made asfollows:

Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified waterto total 5 ml

The active ingredient is passed through a No. 45 U.S. sieve, and mixedwith the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution and flavor are diluted with a portionof the water and added, with stirring. Sufficient water is then added toproduce the required volume.

Formulation Example 8

An intravenous formulation may be prepared as follows:

Active ingredient  100 mg Saturated fatty acid glycerides 1000 ml

The solution of the above ingredients is generally administeredintravenously to a subject at a rate of 1 ml per minute.

1. A compound of the formula:

(wherein: R¹ is benzyl substituted with halogen; R² is hydrogen or loweralkyl; R³ is optionally substituted alkyl (substituent: lower alkoxy,amino optionally substituted with lower alkyl, cyano, hydroxy, carboxy,or lower alkoxycarbonyl) or optionally substituted amino (substituent:lower alkyl); R⁴ is optionally substituted carboxy (substituent: loweralkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, optionallysubstituted amino lower alkyl, or an optionally substituted heterocyclicgroup), optionally substituted formylamino (substituent: lower alkyl,hydroxy lower alkyl, lower alkoxy lower alkyl, optionally substitutedcarbamoyl lower alkyl, optionally substituted lower alkoxy, optionallysubstituted amino, or optionally substituted carbamoyl), optionallysubstituted carbamoyl (substituent: lower alkyl, optionally substitutedlower alkyl (substituent: hydroxy, lower alkoxy, optionally substitutedamino, optionally substituted lower alkoxy, carbamoyl), or optionallysubstituted heterocyclic group lower alkyl), optionally substitutedalkyl (substituent: hydroxy, halogen, an optionally substitutedheterocyclic group, optionally substituted lower alkoxy, optionallysubstituted amino, optionally substituted carbamoyl, or optionallysubstituted carboxy), or optionally substituted alkenyl (substituent:hydroxy, halogen, an optionally substituted heterocyclic group,optionally substituted lower alkoxy, optionally substituted amino,optionally substituted carbamoyl, or optionally substituted carboxy)),or a pharmaceutically acceptable salt thereof (except for Compound (I-A)shown in Table 1 below) TABLE 1 (I-A)

Compound No. R² R³ R⁴ 20 H CH2CH2OMe H 27 H Me NHMs 28 H CH2CH2OMe NHMs29 H i-Pr NHMs 85 Me Me H 86 H NHMe H 87 H NMe2 H 88 H OMe H 89 H H H 90H Me H 91 H Et H 92 H i-Pr H 126 H CH2CH2NMe2 H 160 H CH2CH2OMeNHCOCH2OMe 161 H CH2CH2OMe NHCOCH2CH2CO2Et 162 H CH2CH2OMe NHCOCH2CO2Et163 H CH2CH2OMe NHCOOEt 164 H CH2CH2OMe NHCOCH2CH2OMe 165 H CH2CH2OMeNHCO-thiophene 180 H CH2CH2OMe Ph-CH2OH 181 H NMe2 Ph-CH2OH (Me =methyl; i-Pr = isopropyl; Et = ethyl; Ms = methanesulfonyl; thiophene =thiophene; Ph = phenyl).


2. The compound according to claim 1, wherein R¹ is p-fluorobenzyl, or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R² is hydrogen; R³ is CH₂CH₂OCH₃, CH₂CH₂OEt,CH₂CH₂COOCH₃, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂O(i-Pr), N(CH₃)₂, CH₂CH₂CN,CH₂CH₂N(CH₃)₂, CH₂CH₂N(i-Pr)₂, CH₂CH₂CH₂N(CH₃)₂, CH₂CH₂CH₂N(Et)₂,CH(CH₃)CH₂OH, CH(CH₃)COOCH₃ or CH₂CH(OH)CH₂CH₃, or a pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 1, whereinR⁴ is a group shown below, or a pharmaceutically acceptable salt thereof

(wherein, Me is methyl; Ac is acetyl; Ms is methanesulfonyl).
 5. Thecompound according to claim 4, wherein R¹ is p-fluorobenzyl, or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 4, wherein R^(l) is p-fluorobenzyl; R² is hydrogen; R³ isCH₂CH₂OCH₃, N(CH₃)₂, CH₂CH₂CN, CH₂CH₂N(CH₃)₂, CH₂CH₂CH₂N(CH₃)₂, orCH₂CH(OH)CH₂CH₃; or a pharmaceutically acceptable salt thereof.